G2Cdb::Gene report

Gene id
G00001666
Gene symbol
MAOA (HGNC)
Species
Homo sapiens
Description
monoamine oxidase A
Orthologue
G00000417 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000021387 (Vega human gene)
Gene
ENSG00000189221 (Ensembl human gene)
4128 (Entrez Gene)
762 (G2Cdb plasticity & disease)
MAOA (GeneCards)
Literature
309850 (OMIM)
Marker Symbol
HGNC:6833 (HGNC)
Protein Sequence
P21397 (UniProt)

Literature (303)

Pubmed - other

  • Lack of association between schizophrenia and polymorphisms in dopamine metabolism and transport genes.

    Alvarez S, Mas S, Gassó P, Bernardo M, Parellada E and Lafuente A

    Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Casanova 143, E-08036 Barcelona, Spain.

    We investigated the relationship between several functional polymorphisms in genes coding for dopamine metabolism and transport enzymes (MAO-A VNTR; MAO-A 941T>G; DAT VNTR; DAT -67A/T; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*6) and the frequency of schizophrenia. Participants in the study were 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls. Genomic DNA was isolated from whole blood and genotyped by several methods. However, there was no association between schizophrenia and the alleles, genotypes or diplotypes that were studied or their interactions. Polymorphisms in genes coding for dopamine metabolism and transport enzymes did not predispose to or protect from schizophrenia and related disorders.

    Fundamental & clinical pharmacology 2010;24;6;741-7

  • Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior.

    Wakschlag LS, Kistner EO, Pine DS, Biesecker G, Pickett KE, Skol AD, Dukic V, Blair RJ, Leventhal BL, Cox NJ, Burns JL, Kasza KE, Wright RJ and Cook EH

    Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA. lwakschlag@psych.uic.edu

    Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene x exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene x exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene x exposure interactions may shape behavior through associated changes in brain function.

    Funded by: Department of Health: CSA/03/07/014; Intramural NIH HHS: ZIA MH002780-08, ZIA MH002781-08, ZIA MH002782-08; NIDA NIH HHS: DA015223-01A1, DA015223-02, DA015223-03, DA015223-04, DA015223-04S1, DA015223-05, DA015223-06, DA15223, R01 DA015223, R01 DA015223-01A1, R01 DA015223-02, R01 DA015223-03, R01 DA015223-04, R01 DA015223-04S1, R01 DA015223-05, R01 DA015223-06

    Molecular psychiatry 2010;15;9;928-37

  • MAOA-uVNTR and early physical discipline interact to influence delinquent behavior.

    Edwards AC, Dodge KA, Latendresse SJ, Lansford JE, Bates JE, Pettit GS, Budde JP, Goate AM and Dick DM

    Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.

    Background: A functional polymorphism in the promoter region of the monoamine oxidizing gene monoamine oxidase A (MAOA) has been associated with behavioral sensitivity to adverse environmental conditions in multiple studies (e.g., Caspi et al. 2002; Kim-Cohen et al., 2006). The present study investigates the effects of genotype and early physical discipline on externalizing behavior. We expand on the current literature in our assessment of externalizing, incorporating information across multiple reporters and over a broad developmental time period, and in our understanding of environmental risk.

    Method: This study uses data from the Child Development Project, an ongoing longitudinal study following a community sample of children beginning at age 5. Physical discipline before age 6 was quantified using a subset of questions from the Conflict Tactics Scale (Straus, 1979). Externalizing behavior was assessed in the male, European-American sub-sample (N = 250) by parent, teacher, and self-report using Achenbach's Child Behavior Checklist, Teacher Report Form, and Youth Self-Report (Achenbach, 1991), at 17 time points from ages 6 to 22. Regression analyses tested the influence of genotype, physical discipline, and their interaction on externalizing behavior, and its subscales, delinquency and aggression.

    Results: We found a significant interaction effect between genotype and physical discipline on levels of delinquent behavior. Similar trends were observed for aggression and overall externalizing behavior, although these did not reach statistical significance. Main effects of physical discipline held for all outcome variables, and no main effects held for genotype.

    Conclusion: The adverse consequences of physical discipline on forms of externalizing behavior are exacerbated by an underlying biological risk conferred by MAOA genotype.

    Funded by: NIAAA NIH HHS: AA-15416, K02 AA018755, R01 AA015416, R01 AA015416-06; NICHD NIH HHS: R01 HD030572; NIDA NIH HHS: 5R01DA16903, DA015226, DA016903, DA017589, K05 DA015226, P20 DA017589, R01 DA016903; NIMH NIH HHS: 3 R01 MH057024-07S1, MH56961, MH57024, MH57095, R01 MH042498, R01 MH056961, R01 MH057024, R01 MH057095

    Journal of child psychology and psychiatry, and allied disciplines 2010;51;6;679-87

  • Catechol-o-methyltransferase genotype and childhood trauma may interact to impact schizotypal personality traits.

    Savitz J, van der Merwe L, Newman TK, Stein DJ and Ramesar R

    MRC/UCT Human Genetics Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. savitzj@mail.nih.gov

    We attempt to identify gene by childhood abuse interactions which predispose to the development of schizotypal traits in a familial bipolar disorder (BD) sample. Self-report measures of schizotypal personality traits (Schizotypal Personality Scale) and childhood maltreatment (Childhood Trauma Questionnaire) were administered to 222 participants from 44 families with BD. Variants of catechol-o-methyltransferase (COMT) and four other dopamine pathway-related genes: DRD4, DRD2,MAOA, and SLC6A3, were typed. BD type I (BD I) subjects scored significantly higher than their unaffected relatives on the Schizotypal Personality Scale. The val allele of the Val158 Met polymorphism of the COMT gene was associated with increased schizotypal personality trait scores in individuals exposed to higher levels of self-reported childhood trauma (p < 0.05). There was no direct effect of the val158met polymorphism on schizotypal personality traits. Further, no passive correlation between COMT genotype and childhood trauma was found. We raise the possibility that genetically-driven variation in COMT may interact with childhood trauma to contribute to the risk of developing schizotypal personality traits.

    Behavior genetics 2010;40;3;415-23

  • Gene-gene interaction between COMT and MAOA potentially predicts the intelligence of attention-deficit hyperactivity disorder boys in China.

    Qian QJ, Yang L, Wang YF, Zhang HB, Guan LL, Chen Y, Ji N, Liu L and Faraone SV

    Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Peking University, 100191, Beijing, China.

    The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism (Val158Met) affecting the activity of the enzyme, and the monoamine oxidase A (MAOA) gene contains a VNTR polymorphism (MAOA-uVNTR) that affects the transcription of the gene. COMT and MAOA each contribute to the enzymatic degradation of dopamine and noradrenaline. Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities, including intelligence, is modulated by dopamine. Since our previous association studies between attention deficit hyperactivity disorder (ADHD) and these two functional polymorphisms consistently showed the low activity alleles were preferentially transmitted to inattentive ADHD boys, the goal of the present study was to test the hypothesis that the interaction between COMT Val158Met and MAOA-uVNTR may affect the intelligence in a clinical sample of Chinese male ADHD subjects (n = 264). We found that the COMT x MAOA interaction significantly predicted full scale (FSIQ) and performance (PIQ) IQ scores (P = 0.039, 0.011); the MAOA-uVNTR significantly predicted FSIQ, PIQ and verbal IQ (VIQ) (P = 0.009, 0.019, 0.038); COMT Val158Met independently had no effect on any of the IQ scores. Only the COMT x MAOA interaction for PIQ remained significant after a Bonferroni correction. Among all combined genotypes, the valval-3R genotype predicted higher intelligence, (average 106.7 +/- 1.6, 95% C.I. 103.7-109.8 for FSIQ), and the valval-4R predicted lower intelligence (average 98.0 +/- 2.3, 95% C.I. 93.5-102.6 for FSIQ). These results suggest that there is an inverted U-shaped relationship between intelligence and dopaminergic activity in our sample. Our finding that gene-gene interaction between COMT and MAOA predicts the intelligence of ADHD boys in China is intriguing but requires replication in other samples.

    Behavior genetics 2010;40;3;357-65

  • A population-based association study of candidate genes for depression and sleep disturbance.

    Utge S, Soronen P, Partonen T, Loukola A, Kronholm E, Pirkola S, Nyman E, Porkka-Heiskanen T and Paunio T

    Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    The clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic-pituitary-adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population-based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation-based allelic association analysis of a sample of 1,654 adults recruited from Finland's population-based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex-dependent and symptom-specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010;153B;2;468-476

  • The intersection of genes and neuropsychological deficits in the prediction of adolescent delinquency and low self-control.

    Beaver KM, DeLisi M, Vaughn MG and Wright JP

    Florida State University, College of Criminology and Criminal Justice, 634 West Call Street, Tallahassee, FL 32306-1127, USA. kbeaver@fsu.edu

    Gottfredson and Hirschi's A General Theory of Crime, Moffitt's developmental taxonomy theory, and Caspi et al.'s Gene x Environment study are three of the most influential pieces of contemporary criminological scholarship. Even so, there has been little attempt to integrate and empirically assess these three perspectives simultaneously. This article addresses this gap in the literature by analyzing phenotypic and genotypic data from the National Longitudinal Study of Adolescent Health (Add Health). The results revealed that all three perspectives have considerable empirical support, where neuropsychological deficits interact with the MAOA genotype to predict adolescent delinquency and levels of self-control for White males. The theoretical implications of the findings are noted.

    International journal of offender therapy and comparative criminology 2010;54;1;22-42

  • Genetic susceptibility to distinct bladder cancer subphenotypes.

    Guey LT, García-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M, Rothman N, Vellalta G, Calle ML, Marenne G, Tardón A, Carrato A, García-Closas R, Serra C, Silverman DT, Chanock S, Real FX, Malats N and EPICURO/Spanish Bladder Cancer Study investigators

    Spanish National Cancer Research Centre, Madrid, Spain.

    Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes.

    Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity.

    The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n=1149).

    Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n=586), high-grade nonmuscle invasive (n=219), and muscle invasive (n=246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested.

    Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate.

    Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.

    Funded by: Intramural NIH HHS: ZIA CP010136-16

    European urology 2010;57;2;283-92

  • Meta-analysis of the association between the monoamine oxidase-A gene and mood disorders.

    Fan M, Liu B, Jiang T, Jiang X, Zhao H and Zhang J

    National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, PR China.

    Objective: To evaluate the controversial, putative associations between the three common polymorphisms [promoter variable number tandem repeat (uVNTR), T941G, (CA) repeat] of monoamine oxidase A (MAOA) and mood disorders (major depressive or bipolar disorders, BPD) by systematically meta-analyzing published case-control association studies.

    Methods: We queried PubMed using the keywords 'MAOA', 'association' and 'depression' or 'bipolar'. Nine studies on uVNTR, seven studies on T941G, and eight studies on CA met the inclusion criteria. The meta-analysis was performed by sex and ethnicity.

    Our meta-analysis showed a significant association between uVNTR and MDD for the Asian group [odds ratio (OR) = 1.23 (1.02-1.47), P=0.03] and male Asian group [OR = 1.47 (1.06-2.05), P=0.02]. For the CA polymorphism, we found a significant association with BPD in the Caucasian group [OR = 1.28 (1.01-1.62), P=0.04] and female Caucasian group [OR = 1.36 (1.031-1.81), P=0.03]. For the CA polymorphism, we identified significant associations with BPD in all Caucasians for the overall alleles and for the specific alleles in a6 [OR = 1.35 (1.11-1.64), P=0.002] and in female Caucasians for the overall alleles and for the specific alleles in a2 [OR = 0.65 (0.48-0.90), P=0.009], a5 [OR = 1.44 (1.04-1.99), P=0.03], and a6 [OR = 1.41(1.12-1.78), P=0.004].

    Conclusion: Our meta-analysis suggests a significant association of the MAOA gene with major depressive disorder and BPD within specific groups, indicating that these three polymorphisms of the MAOA gene may be associated with mood disorders by sex and ethnicity. Moreover, our systematic meta-analysis has revealed that although MAOA may be a common candidate gene for mood disorders, different polymorphisms and alleles appear to play different roles in major depressive disorder and BPD.

    Psychiatric genetics 2010;20;1;1-7

  • Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines.

    Tu HP, Ko AM, Wang SJ, Lee CH, Lea RA, Chiang SL, Chiang HC, Wang TN, Huang MC, Ou TT, Lin GT and Ko YC

    Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. p915013@kmu.edu.tw

    Taiwanese aborigines have a high prevalence of hyperuricemia and gout. Uric acid levels and urate excretion have correlated with dopamine-induced glomerular filtration response. MAOs represent one of the major renal dopamine metabolic pathways. We aimed to identify the monoamine oxidase A (MAOA, Xp11.3) gene variants and MAO-A enzyme activity associated with gout risk. This study was to investigate the association between gout and the MAOA single-nucleotide polymorphisms (SNPs) rs5953210, rs2283725, and rs1137070 as well as between gout and the COMT SNPs rs4680 Val158Met for 374 gout cases and 604 controls. MAO-A activity was also measured. All three MAOA SNPs were significantly associated with gout. A synonymous MAOA SNP, rs1137070 Asp470Asp, located in exon 14, was associated with the risk of having gout (P = 4.0 x 10(-5), adjusted odds ratio 1.46, 95% confidence intervals [CI]: 1.11-1.91). We also showed that, when compared to individuals with the MAOA GAT haplotype, carriers of the AGC haplotype had a 1.67-fold (95% CI: 1.28-2.17) higher risk of gout. Moreover, we found that MAOA enzyme activity correlated positively with hyperuricemia and gout (P for trend = 2.00 x 10(-3) vs. normal control). We also found that MAOA enzyme activity by rs1137070 allele was associated with hyperuricemia and gout (P for trend = 1.53 x 10(-6) vs. wild-type allele). Thus, our results show that some MAOA alleles, which have a higher enzyme activity, predispose to the development of gout.

    Human genetics 2010;127;2;223-9

  • Lack of association between antipsychotic-induced extrapyramidal symptoms and polymorphisms in dopamine metabolism and transport genes.

    Gassó P, Mas S, Crescenti A, Alvarez S, Parramon G, Garcia-Rizo C, Parellada E, Bernardo M and Lafuente A

    Dept. Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.

    The purpose of this study was to investigate the relationship between functional polymorphisms in genes coding for dopamine metabolism and transport enzymes and the incidence of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS). We did not find evidence of the involvement of these polymorphisms in the predisposition towards or protection from EPS.

    Psychiatry research 2010;175;1-2;173-5

  • Association study of the serotoninergic system in migraine in the Spanish population.

    Corominas R, Sobrido MJ, Ribasés M, Cuenca-León E, Blanco-Arias P, Narberhaus B, Roig M, Leira R, López-González J, Macaya A and Cormand B

    Grup de Recerca en Neurologia Infantil i Psiquiatria Genètica, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

    In order to evaluate the contribution of 19 serotonin-related genes to the susceptibility to migraine in a Spanish population we performed a case-control association study of 122 single nucleotide polymorphisms (SNPs), selected according to genetic coverage parameters, in 528 migraine patients -308 with migraine without aura (MO) and 220 with migraine with aura (MA)- and 528 sex-matched migraine-free controls. The single-marker analysis identified nominal associations with the migraine phenotype or with the MO or MA subtypes. The multiple-marker analysis revealed risk haplotypes in three genes that remained significantly associated with migraine after correction by permutations. Two-marker risk haplotypes were identified in the HTR2B (rs16827801T-rs10194776G) and MAOA (rs3027400G-rs2072743C) genes conferring susceptibility to MO, and a four-marker haplotype in DDC was specific of MA (rs2329340A-rs11974297C-rs2044859T-rs11761683G). The present study supports the involvement of HTR2B and MAOA genes in the genetic predisposition to MO, while DDC might confer susceptibility to MA. These results suggest a differential involvement of serotonin-related genes in the genetic background of MO and MA.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010;153B;1;177-84

  • Monoamine oxidase A gene (MAOA) associated with attitude towards longshot risks.

    Zhong S, Israel S, Xue H, Ebstein RP and Chew SH

    Center for Experimental Business Research and Department of Economics, Hong Kong University of Science and Technology, Kowloon, Hong Kong Special Administrative Region, Hong Kong.

    Decision making often entails longshot risks involving a small chance of receiving a substantial outcome. People tend to be risk preferring (averse) when facing longshot risks involving significant gains (losses). This differentiation towards longshot risks underpins the markets for lottery as well as for insurance. Both lottery and insurance have emerged since ancient times and continue to play a useful role in the modern economy. In this study, we observe subjects' incentivized choices in a controlled laboratory setting, and investigate their association with a widely studied, promoter-region repeat functional polymorphism in monoamine oxidase A gene (MAOA). We find that subjects with the high activity (4-repeat) allele are characterized by a preference for the longshot lottery and also less insurance purchasing than subjects with the low activity (3-repeat) allele. This is the first result to link attitude towards longshot risks to a specific gene. It complements recent findings on the neurobiological basis of economic risk taking.

    PloS one 2009;4;12;e8516

  • Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.

    Treister R, Pud D, Ebstein RP, Laiba E, Gershon E, Haddad M and Eisenberg E

    The Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

    Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n=192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 degrees C) and phasic heat pain (47 degrees C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine-related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A), 40-bp repeat in the 3'-untranslated region of the dopamine transporter gene (DAT-1), and 48-bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT-1 (p=0.008) and MAO-A (p=0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.

    Pain 2009;147;1-3;187-93

  • A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms.

    Gassó P, Mas S, Bernardo M, Alvarez S, Parellada E and Lafuente A

    Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.

    We present a pharmacogenetic study of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS) using an extensive linkage disequilibrium mapping approach in seven-candidate genes with a well-established link to dopamine (DRD2, DRD3, ACE, COMT, DAT, MAO-A, MAO-B). From a cohort of 321 psychiatric inpatients, 81 cases presenting with EPS (Simpson-Angus > 3) and 189 controls presenting without EPS (Simpson-Angus < or = 3) took part. Eighty-four-tag single nucleotide polymorphisms (SNPs) in candidate genes were genotyped. After extensive data cleaning, 70 SNPs were analyzed for association of single markers and haplotypes. AP dosage, AP-DRD2 blockade potency and age were identified as susceptibility factors for AP-induced EPS. One SNP of the DRD3 gene, rs167771, achieved significant association with EPS risk after Bonferroni correction (nominal P-value 1.3 x 10(-4)) in the patients treated with risperidone (132 patients). AP-induced EPS remains a serious public health problem. Our finding of a common SNP (rs167771) in the DRD3 gene provides a strong new candidate gene for risperidone-induced EPS.

    The pharmacogenomics journal 2009;9;6;404-10

  • Psychopathy trait scores in adolescents with childhood ADHD: the contribution of genotypes affecting MAOA, 5HTT and COMT activity.

    Fowler T, Langley K, Rice F, van den Bree MB, Ross K, Wilkinson LS, Owen MJ, O'Donovan MC and Thapar A

    Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.

    Objectives: Psychopathy-related traits, especially those tapping the 'emotional dysfunction' aspect of psychopathy that is characterized by lack of emotional responsiveness, are thought to be of genetic origin, but molecular genetic studies are yet to be undertaken. Gene variants that affect COMT, MAOA and 5HTT activity have previously been linked to antisocial behaviour. The aims of this study were to test whether these gene variants are linked to psychopathy traits in attention-deficit hyperactivity disorder (ADHD).

    Methods: Adolescents were followed up 5 years after an initial diagnosis of ADHD. Psychopathy trait scores were assessed [total scores and 'emotional dysfunction' (also referred to as 'affective') scores] and the MAOA 30-bp variable number of tandem repeats, SLC6A4 44-bp insertion/deletion and COMT Val158Met variants were genotyped.

    Results: All three gene variants were associated with 'emotional dysfunction' scores. MAOA and 5HTT variants were associated with total psychopathy scores. The results were not explained by associated conduct disorder.

    Conclusion: The results suggest that specific gene variants influence psychopathy traits in ADHD.

    Funded by: Department of Health; Wellcome Trust: 059870

    Psychiatric genetics 2009;19;6;312-9

  • Sex-specific interaction between MAOA promoter polymorphism and Apo epsilon 2 allele in major depressive disorder in the Chinese population.

    Lin CH, Chang YY and Lung FW

    Psychiatric genetics 2009;19;6;337

  • Genetical genomic determinants of alcohol consumption in rats and humans.

    Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob G, Richardson HN, Kechris K, Bell RL, Hübner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL and WHO/ISBRA Study on State and Trait Markers of Alcoholism

    Department of Pharmacology, University of Colorado, Denver, Aurora, CO, USA. boris.tabakoff@ucdenver.edu

    Background: We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.

    Results: In the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.

    Conclusion: Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.

    Funded by: Howard Hughes Medical Institute; NHLBI NIH HHS: HL35018, P01 HL035018; NIAAA NIH HHS: AA006420, AA013162, AA013517-INIA, AA013522-INIA, AA016649-INIA, AA016663-INIA, AA16922, K01 AA016922, P50 AA006420, P60 AA006420, R01 AA013162, R24 AA013162, R24 AA015512, U01 AA013517, U01 AA013522, U01 AA016649, U01 AA016663, U24 AA013517, U24 AA013522; NIDDK NIH HHS: R01 DK100340; Wellcome Trust

    BMC biology 2009;7;70

  • Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study.

    Gallicchio L, Chang HH, Christo DK, Thuita L, Huang HY, Strickland P, Ruczinski I, Clipp S and Helzlsouer KJ

    The Prevention and Research Center, The Weinberg Center for Women's Health & Medicine, Mercy Medical Center, Baltimore, Maryland 21202, USA. lgallic@mdmercy.com

    Background: The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time.

    Methods: Data were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-alpha (TNFalpha), and peroxisome proliferative activated receptor-gamma and -delta (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes.

    Results: The results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFalpha rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101).

    Conclusion: Findings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.

    Funded by: NIA NIH HHS: 1U01AG18033, U01 AG018033

    BMC medical genetics 2009;10;103

  • The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT.

    Doornbos B, Dijck-Brouwer DA, Kema IP, Tanke MA, van Goor SA, Muskiet FA and Korf J

    Graduate School of Behavioral and Cognitive Neuroscience, University Center for Psychiatry, University Medical Center Groningen, The Netherlands. b.doornbos@med.umcg.nl

    Background: Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction.

    Methods: Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed.

    Results: We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p<0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum.

    Conclusion: We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

    Progress in neuro-psychopharmacology & biological psychiatry 2009;33;7;1250-4

  • The interleukin-6, serotonin transporter, and monoamine oxidase A genes and endurance performance during the South African Ironman Triathlon.

    de Milander L, Stein DJ and Collins M

    UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

    Previous studies have identified an association of genetic variants believed to alter physiological and biochemical processes locally within the skeletal muscle and therefore performance in the Ironman triathlon. There is growing evidence that the serotonergic system and circulating interleukin (IL)-6 levels are also involved in mediating endurance capacity. Investigators have demonstrated that recombinant human IL-6 administration and serotonergic neurotransmission manipulation, with 5-hydroxytryptamine transporter (5-HTT) and monoamine oxidase A (MAO-A) inhibitors, prior to exercise, can alter running performance, consistent with a central governor hypothesis. The aim of this study was to investigate possible associations of functional polymorphisms within the IL-6, 5-HTT, and MAO-A genes with endurance performance of Ironman triathletes. Four hundred sixty-eight male Caucasian triathletes who completed the 2000 and (or) 2001 South African Ironman Triathlon and 200 healthy Caucasian male controls were genotyped for the -174 IL-6 G/C, 5-HTT 40 base pair (bp) insertion-deletion and 30 bp variable number of tandem repeats (VNTR) MAO-A gene polymorphisms. There were no significant differences in the relative genotype distributions within the IL-6 (p = 0.636), 5-HTT (p = 0.659), and MOA-A (p = 0.227) polymorphisms when the fastest-fnishing, middle-finishing, and slowest-finishing triathletes, as well as the control groups, were compared. There were no direct associations between the IL-6 -174 G/C, 5-HTT 44 bp insertion-deletion, and MAO-A 30 bp VNTR gene polymorphisms and endurance performance in the 2000 and (or) 2001 South African Ironman Triathlons. The neurogenetic basis of the central governor requires further investigation.

    Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 2009;34;5;858-65

  • Negative emotionality: monoamine oxidase B gene variants modulate personality traits in healthy humans.

    Dlugos AM, Palmer AA and de Wit H

    Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, 5841 S. Maryland Ave, Chicago, IL, USA. andrea.dlugos@ukmuenster.de

    Monoamine oxidase A and B (MAOA and MAOB) appear to be involved in the pathogenesis of Major Depression, and vulnerability of Major Depression is associated with personality traits relating to positive and negative affect. This study aimed to investigate associations between MAOA and MAOB polymorphisms and personality traits of positive and negative emotionality in healthy volunteers, to elucidate mechanisms underlying personality and the risk for depression. Healthy Caucasian volunteers (N = 150) completed the Multiphasic Personality Questionnaire (MPQ), which includes independent superfactors of Positive Emotionality and Negative Emotionality. Participants were genotyped for 8 MAOA and 12 MAOB single nucleotide polymorphisms (SNPs). Association analyses for both SNPs and haplotypes were performed using the permutation approach implemented in PLINK. Negative Emotionality was significantly associated with the two highly linked MAOB polymorphisms rs10521432 and rs6651806 (p < 0.002). Findings were extended in haplotype analyses. For MAOB the 4-SNP haplotype GACG formed from rs1799836, rs10521432, rs6651806 and rs590551 was significantly related to lower Negative Emotionality scores (p < 0.002). MAOA was not related to personality in this study. Our finding provides the first evidence that MAOB polymorphisms influence levels of negative emotionality in healthy human volunteers. If confirmed, these results could lead to a better understanding of personality traits and inter-individual susceptibility developing psychiatric disorders such as major depression.

    Funded by: NCRR NIH HHS: M0 RR00055, M01 RR000055; NIDA NIH HHS: DA021336, DA02812, R01 DA002812, R01 DA021336

    Journal of neural transmission (Vienna, Austria : 1996) 2009;116;10;1323-34

  • Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves.

    Peña-Silva RA, Miller JD, Chu Y and Heistad DD

    Departments of Pharmacology, University of Iowa Carver College of Medicine, Iowa City School of Medicine, Iowa City, Iowa 52242, USA. ricardo-pena@uiowa.edu

    Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2*.-) was measured in heart valves from explanted human hearts that were not used for transplantation. (O2*.-) levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in (O2*.-). Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased (O2*.-) levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in (O2*.-) during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated (O2*.-), and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

    Funded by: NHLBI NIH HHS: HL-092235, HL-62984; NINDS NIH HHS: NS-24621

    American journal of physiology. Heart and circulatory physiology 2009;297;4;H1354-60

  • Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

    Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A and Psychiatric Genetics Network Group

    CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

    A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;6;808-16

  • Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene.

    Roe BE, Tilley MR, Gu HH, Beversdorf DQ, Sadee W, Haab TC and Papp AC

    Department of Agricultural, Environmental and Development Economics, Ohio State University, Columbus, Ohio, USA. roe.30@osu.edu

    With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes.

    Funded by: NCRR NIH HHS: UL1 RR025755, UL1RR025755; NIDA NIH HHS: DA020124, DA022199, R01 DA020124, R01 DA022199; NINDS NIH HHS: K23 NS043222, K23 NS43222

    PloS one 2009;4;8;e6704

  • High activity of monoamine oxidase A is associated with externalizing behaviour in maltreated and nonmaltreated adoptees.

    van der Vegt EJ, Oostra BA, Arias-Vásquez A, van der Ende J, Verhulst FC and Tiemeier H

    Department of Child and Adolescent Psychiatry, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.

    Individual differences in a functional polymorphism of the promoter of the Monoamine oxidase A (MAO-A) gene might partly explain the increased vulnerability of maltreated children for externalizing behaviour. A sample of 239 internationally adopted boys was studied. Adoptive parents provided the information about abuse and neglect before the adoption and rated externalizing behaviour of their adopted children, using the Child Behaviour Checklist. MAO-A alleles were classified in high and low activity. We found that individuals with high MAO-A activity had more externalizing behaviour than those with low MAO-A activity. No modifying effect of MAO-A on the relationship between early maltreatment on externalizing behaviour was observed. Our results suggest that in severely maltreated children, high MAO-A activity may not protect against the effects of maltreatment but may convey an increased risk for externalizing behaviour.

    Psychiatric genetics 2009;19;4;209-11

  • Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder.

    Leuchter AF, McCracken JT, Hunter AM, Cook IA and Alpert JE

    Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA,760 Westwood Plaza, Rm 37-452, Los Angeles, CA 90024-1759, USA. afl@ucla.edu

    The placebo response shows pronounced interindividual variability. Placebos are postulated to act through central reward pathways that are modulated by monoamines. Because monoaminergic signaling is under strong genetic control, we hypothesized that common functional polymorphisms modulating monoaminergic tone would be related to degree of improvement during placebo treatment of subjects with major depressive disorder. We examined polymorphisms in genes encoding the catabolic enzymes catechol-O-methyltransferase and monoamine oxidase A. Subjects with monoamine oxidase A G/T polymorphisms (rs6323) coding for the highest activity form of the enzyme (G or G/G) had a significantly lower magnitude of placebo response than those with other genotypes. Subjects with ValMet catechol-O-methyltransferase polymorphisms coding for a lower-activity form of the enzyme (2 Met alleles) showed a statistical trend toward a lower magnitude of placebo response. These findings support the hypothesis that genetic polymorphisms modulating monoaminergic tone are related to degree of placebo responsiveness in major depressive disorder.

    Funded by: NCCIH NIH HHS: R01 AT002479

    Journal of clinical psychopharmacology 2009;29;4;372-7

  • Mutagenic probes of the role of Ser209 on the cavity shaping loop of human monoamine oxidase A.

    Wang J, Harris J, Mousseau DD and Edmondson DE

    Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.

    The available literature implicating human monoamine oxidase A (MAO A) in apoptotic processes reports levels of MAO A protein that do not correlate with activity, suggesting that unknown mechanisms may be involved in the regulation of catalytic function. Bioinformatic analysis suggests Ser209 as a possible phosphorylation site that may be relevant to catalytic function because it is adjacent to a six-residue loop termed the 'cavity shaping loop' from structural data. To probe the functional role of this site, MAO A Ser209Ala and Ser209Glu mutants were created and investigated. In its membrane-bound form, the MAO A Ser209Glu phosphorylation mimic exhibits catalytic and inhibitor binding properties similar to those of wild-type MAO A. Solubilization in detergent solution and purification of the Ser209Glu mutant results in considerable decreases in these functional parameters. By contrast, the MAO A Ser209Ala mutant exhibits similar catalytic properties to those of wild-type enzyme when purified. Compared to purified wild-type and Ser209Ala MAO A proteins, the Ser209Glu MAO A mutant shows significant differences in covalent flavin fluorescence yield, CD spectra and thermal stability. These structural differences in the purified MAO A Ser209Glu mutant are not exhibited in quantitative structure-activity relationship patterns using a series of para-substituted benzylamine analogs similar to the wild-type enzyme. These data suggest that Ser209 in MAO A does not appear to be the putative phosphorylation site for regulation of MAO A activity and demonstrate that the membrane environment plays a significant role in stabilizing the structure of MAO A and its mutant forms.

    Funded by: NIGMS NIH HHS: GM-29433, R01 GM029433, R01 GM029433-26

    The FEBS journal 2009;276;16;4569-81

  • Calcium alters monoamine oxidase-A parameters in human cerebellar and rat glial C6 cell extracts: possible influence by distinct signalling pathways.

    Cao X, Li XM and Mousseau DD

    Cell Signalling Laboratory, Department of Psychiatry, B45 HSB, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada.

    Aims: Calcium (Ca(2+)) is known to augment monoamine oxidase-A (MAO-A) activity in cell cultures as well as in brain extracts from several species. This association between Ca(2+) and MAO-A could contribute to their respective roles in cytotoxicity. However, the effect of Ca(2+) on MAO-A function in human brain has as yet to be examined as does the contribution of specific signalling cascades.

    We examined the effects of Ca(2+) on MAO-A activity and on [(3)H]Ro 41-1049 binding to MAO-A in human cerebellar extracts, and compared this to its effects on MAO-A activity in glial C6 cells following the targeting of signalling pathways using specific chemical inhibitors.

    Ca(2+) enhances MAO-A activity as well as the association of [(3)H]Ro 41-1049 to MAO-A in human cerebellar extracts. The screening of neuronal and glial cell cultures reveals that MAO-A activity does not always correlate with the expression of either mao-A mRNA or MAO-A protein. Inhibition of the individual PI3K/Akt, ERK and p38(MAPK) signalling pathways in glial C6 cells all augment basal MAO-A activity. Inhibition of the p38(MAPK) pathway also augments Ca(2+)-sensitive MAO-A activity. We also observe the inverse relation between p38(MAPK) activation and MAO-A function in C6 cultures grown to full confluence.

    Significance: The Ca(2+)-sensitive component to MAO-A activity is present in human brain and in vitro studies link it to the p38(MAPK) pathway. This means of influencing MAO-A function could explain its role in pathologies as diverse as neurodegeneration and cancers.

    Life sciences 2009;85;5-6;262-8

  • Candidate gene studies of ADHD: a meta-analytic review.

    Gizer IR, Ficks C and Waldman ID

    Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Room 5015 Genetic Medicine Building CB 7264, Chapel Hill, NC 27599-7264, USA. igizer@unc.edu

    Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.

    Funded by: NIAAA NIH HHS: T32 AA007573; NIMH NIH HHS: R13MH59126-0641

    Human genetics 2009;126;1;51-90

  • Monoamine oxidase a promoter gene associated with problem behavior in adults with intellectual/developmental disabilities.

    May ME, Srour A, Hedges LK, Lightfoot DA, Phillips JA, Blakely RD and Kennedy CH

    Southern Illinois University, Illinois, USA.

    A functional polymorphism in the promoter of the gene encoding monoamine oxidase A has been associated with problem behavior in various populations. We examined the association of MAOA alleles in adult males with intellectual/developmental disabilities with and without established histories of problem behavior. These data were compared with a gender, ethnicity, and age-matched contrast sample. About 43% (15/35) of adults with intellectual/developmental disabilities and problem behavior possessed the low-efficiency version of the MAOA gene. In comparison, 20% (7/35) of adults with intellectual/developmental disabilities and no problem behavior and 20% (7/35) of the contrast group had the short-allele MAOA polymorphism. Therefore, a common variant in the MAOA gene may be associated with problem behavior in adults with intellectual/developmental disabilities.

    American journal on intellectual and developmental disabilities 2009;114;4;269-73

  • Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.

    Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP and Goldstein DB

    Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA.

    The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.

    Funded by: NIMH NIH HHS: N01 MH90001

    European journal of human genetics : EJHG 2009;17;7;946-57

  • [Association study of intelligence of attention deficit hyperactivity disorder children in China].

    Qian QJ, Wang YF, Yang L, Li J, Guan LL, Chen Y, Ji N and Liu L

    Department of Pediatrics, Peking University Institute of Mental Health; Key Laboratory of Mental Health, Ministry of Health, Beijing 100191, China.

    Objective: To investigate the association of 5-HT(2A) receptor gene (HTR2A)-1438A/G, Catechol-O-methyltransferase (COMT) gene Val158Met, Monoamine oxidase A ( MAOA ) gene 30 bp-VNTR(MAOA-uVNTR)polymorphisms, and the educational attainment level of the parents with the intelligence of attention deficit hyperactivity disorder (ADHD) in China.

    Methods: A total of 485 DSM-IV ADHD children of Chinese Han descent were included, both complete IQ evaluation, HTR2A-1438A/G, COMT gene Val158Met, and MAOA-uVNTR genotyping results were obtained. The quantitative traits of psychometric IQ were calculated by using the Chinese Wechsler Intelligence Scale for Children (C-WISC). The multifactor linear regression analysis was used to test the associated factors on intelligence.

    Results: Analyses revealed that ADHD children with low enzymatic activity (3R for males, 3R3R for females) of MAOA-uVNTR performed better on Full Scale IQ (FIQ) than did patients with high enzymatic activity (4R for males, 3R4R/4R4R for females) [(102.6+/-12.4) vs (100.3+/-11.7), P=0.078]. The patients with high-enzymatic activity (ValVal) of COMT gene Val158Met performed significantly better on FIQ than did patients with mid-low enzymatic activity (ValMet and MetMet)[(103.5+/-13.6) vs (100.5+/-11.5), P=0.036]. ADHD children with GG genotype of HTR2A-1438A/G performed significantly better on some aspects of C-WISC test (Full Scale IQ and Verbal Scale IQ) than did children with GA and AA genotypes [FIQ :(106.9+/-10.7) vs (100.7+/-12.3) vs (101.7+/-12.9), P=0.003; VIQ: (110.1+/-10.6) vs (103.5+/-12.1) vs (105.1+/-13.2), P=0.001]. The educational attainment level of the parents was associated with all the aspects of C-WISC test (Full Scale IQ, Verbal Scale IQ, and Performance Scale IQ). The multiple linear regression analysis showed that the genotype of HTR2A-1438A/G had significant correlation with FIQ, VIQ and PIQ; while the educational attainment level of the mother had significant correlation with FIQ and VIQ.

    Conclusion: The HTR2A-1438A/G polymorphism and the educational attainment level of the mother were associated with the intelligence of ADHD children in China.

    Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 2009;41;3;285-90

  • A polymorphism of the MAOA gene is associated with emotional brain markers and personality traits on an antisocial index.

    Williams LM, Gatt JM, Kuan SA, Dobson-Stone C, Palmer DM, Paul RH, Song L, Costa PT, Schofield PR and Gordon E

    The Brain Dynamics Centre, Westmead Millennium Institute, Westmead Hospital and Western Clinical School, University of Sydney, Westmead, NSW, Australia. lea_williams@wmi.usyd.edu.au

    Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.

    Funded by: Intramural NIH HHS

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2009;34;7;1797-809

  • Biosocial influences on fraudulent behaviors.

    Beaver KM and Holtfreter K

    Florida State University, College of Criminology and Criminal Justice, Tallahassee 32306, USA. kbeaver@fsu.edu

    A wealth of empirical research has revealed that antisocial behavioral phenotypes result from genetic and environmental factors working independently and interactively. However, much of this research has focused on traditional forms of antisocial behavior, such as aggression and violence. At the same time, research has been slow to examine whether genetic factors may relate to involvement in fraudulent behaviors. This article addresses this gap in the literature and examines whether a polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene interacts with exposure to delinquent peers to predict variation in fraudulent behaviors. Analysis of male participants from the National Longitudinal Study of Adolescent Health (J. R. Udry, 2003) revealed a statistically significant Gene x Environment interaction in which the high-MAOA activity allele increased the odds of fraudulent behaviors, but only among male participants with a high number of delinquent peers.

    Funded by: NICHD NIH HHS: P01-HD31921

    The Journal of genetic psychology 2009;170;2;101-14

  • MAOA gene polymorphisms and response to mirtazapine in major depression.

    Tzeng DS, Chien CC, Lung FW and Yang CY

    Department of Psychiatry, Military Kaohsiung General Hospital, Kaohsiung, Taiwan. tzengds@seed.net.tw

    Background: Polymorphisms in the monoamine oxidase A (MAOA) gene may influence treatment outcomes in major depression disorder (MDD).

    Objective: To investigate the association of MAOA genetic polymorphisms and response to mirtazapine in patients with MDD.

    Method: Fifty-eight adult patients in Taiwan who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic criteria for MDD were given mirtazapine for 7 weeks and evaluated on days 0, 7, 14, 21, 49 using the 24-item Hamilton Rating Scale for Depression (HRSD). Remission was defined as a final HRSD <or= 10 and a 50% reduction in baseline HRSD score. Patients provided venous blood for DNA testing. The patients' response to mirtazapine treatment was compared between those who had the long-form polymorphism in the MAOA gene promoter and the short-form polymorphism.

    Result: The total HRSD scores after mirtazapine treatment were significantly lower than baseline (p < 0.001). There were 10 cases (38.5%) in short from and 6 (18.8%) in long from group touched the remission stage. Patients with the short-form group had a greater response to mirtazapine (p < 0.001) than those with the long-form polymorphism after controlling for age, sex, and apolipoprotein E genetic (APOE) polymorphism.

    Conclusion: The genetic polymorphisms in the MAOA promoter region may be associated with treatment response to mirtazapine.

    Human psychopharmacology 2009;24;4;293-300

  • MAOA is associated with methylphenidate improvement of oppositional symptoms in boys with attention deficit hyperactivity disorder.

    Guimarães AP, Zeni C, Polanczyk G, Genro JP, Roman T, Rohde LA and Hutz MH

    Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

    The monoamine oxidase A (MAOA) gene has been extensively related to aggressive, impulsive and violent behaviours. Previous studies have documented the improvement of oppositional symptoms in attention deficit hyperactivity disorder (ADHD) patients with methylphenidate (MPH). However, the effect of the MAOA gene in response to MPH has not been investigated. A sample of 85 boys from an ADHD outpatient service was genotyped for the MAOA-uVNTR polymorphism. The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale - version IV. The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months of treatment. A significant interaction between the presence of MAOA high-activity genotype and treatment with MPH over time on oppositional scores was detected during the 3 months' treatment (n=85, F2,136=4.83, p=0.009). These results suggest an effect of the MAOA-uVNTR high-activity genotype on the improvement of oppositional symptoms with MPH treatment.

    The international journal of neuropsychopharmacology 2009;12;5;709-14

  • MAOA-uVNTR polymorphism may modify the protective effect of ALDH2 gene against alcohol dependence in antisocial personality disorder.

    Lee SY, Hahn CY, Lee JF, Chen SL, Chen SH, Yeh TL, Kuo PH, Lee IH, Yang YK, Huang SY, Ko HC and Lu RB

    The Institute of Behavioral Medicine, Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 138 Sheng-Li Road, Tainan, Taiwan, Republic of China.

    Background: Antisocial alcoholism is related to dopamine and serotonin which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2). The objective of this study is to determine whether the interaction between the MAOA and the ALDH2 genes is associated with subjects with antisocial personality disorder (ASPD) having alcoholism.

    Methods: A total of 294 Han Chinese men in Taiwan including 132 ASPD with alcoholism (Antisocial ALC) and 162 without alcoholism (Antisocial Non-ALC) were recruited in this study. Alcohol dependence and ASPD were diagnosed according to DSM-IV criteria. Genotypes of ALDH2 and MAOA-uVNTR were determined using PCR-RFLP.

    Results: A significant difference of ALDH2 polymorphisms (p = 3.39E-05), but not of MAOA, was found among the 2 study groups. However, only after the stratification of the MAOA-uVNTR (variable number of tandem repeat located upstream) 3-repeat, a significant association between Antisocial Non-ALC and ALDH2*1/*2 or *2/*2 genotypes was shown (p = 1.46E-05; odds ratio = 3.913); whereas stratification of MAOA-uVNTR 4-repeat revealed no association. Multiple logistic regression analysis further revealed significant interaction of MAOA and ALDH2 gene in antisocial ALC (odds ratio = 2.927; p = 0.032).

    Conclusion: The possible interaction of MAOA and ALDH2 gene is associated with Antisocial ALC in Han Chinese males in Taiwan. However, the protective effects of the ALDH2*2 allele against alcoholism might disappear in subjects with ASPD and carrying MAOA-uVNTR 4-repeat allele in the Han Chinese male population.

    Alcoholism, clinical and experimental research 2009;33;6;985-90

  • Neural mechanisms of anger regulation as a function of genetic risk for violence.

    Alia-Klein N, Goldstein RZ, Tomasi D, Woicik PA, Moeller SJ, Williams B, Craig IW, Telang F, Biegon A, Wang GJ, Fowler JS and Volkow ND

    Medical Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. nellyklein@bnl.gov

    Genetic risk may predispose individuals to compromised anger regulation, potentially through modulation of brain responses to emotionally evocative stimuli. Emphatically expressed, the emotional word No can prohibit behavior through conditioning. In a recent functional magnetic resonance imaging study, the authors showed that healthy males attribute negative valence to No while showing a lateral orbitofrontal response that correlated with their self-reported anger control. Here, the authors examined the influence of the monoamine oxidase A (MAOA) gene (low vs. high transcription variants) on brain response to No and in relationship to trait anger reactivity and control. The orbitofrontal response did not differ as a function of the genotype. Instead, carriers of the low-MAOA genotype had reduced left middle frontal gyrus activation to No compared with the high variant. Furthermore, only for carriers of the up low-MAOA genotype, left amygdala and posterior thalamic activation to No increased with anger reactivity. Thus, vulnerability to aggression in carriers of the low-MAOA genotype is supported by decreased middle frontal response to No and the unique amygdala/thalamus association pattern in this group with anger reactivity but not anger control.

    Funded by: NCRR NIH HHS: M01 RR010710, M01RR10710; NIDA NIH HHS: DA020001-04, K05 DA020001, K05 DA020001-04, K05DA020001

    Emotion (Washington, D.C.) 2009;9;3;385-96

  • Parental care moderates the influence of MAOA-uVNTR genotype and childhood stressors on trait impulsivity and aggression in adult women.

    Kinnally EL, Huang YY, Haverly R, Burke AK, Galfalvy H, Brent DP, Oquendo MA and Mann JJ

    Department of Molecular Imaging and Neuropathology, Columbia University, New York, USA. Ek2500@columbia.edu

    Objectives: Adverse childhood experiences are associated with poor mental health outcomes, including vulnerability to mood disorders and/or antisocial behavior. A functional polymorphism in the regulatory region of the monoamine oxidase A gene (monoamine oxidase A untranslated variable nucleotide tandem repeat, MAOA-uVNTR) may moderate the degree of risk conferred by early trauma. Experiential factors may mitigate or exacerbate the effects of trauma on individuals at genetic risk. We examined the association among MAOA-uVNTR genotype, early stress (family death, family separation, parents' divorce, physical and/or sexual abuse), quality of parental care, and disadvantageous outcomes (trait impulsivity/aggression and depression severity) in adult women.

    Methods: Diagnostic assessments were completed for 159 female participants. All were either healthy or were diagnosed with major depressive disorder or bipolar disorder. Participants were assessed for lifetime trait aggression and impulsiveness and current severity of depression, and were genotyped for the MAOA-uVNTR polymorphism. Participants rated the level of parental care they experienced, and were asked to report specific childhood stressors and abuse.

    Results: High perceived parental care mitigated the effect of a childhood stressor on impulsivity scores in low-expressing MAOA-uVNTR allele carriers, but level of perceived care had no effect in the group homozygous for the high-expressing MAOA-uVNTR allele. Gene-environment interactions did not influence depression severity in the mood disorder group, indicating that the effects of parenting we observed in our participants were independent of depression status.

    Conclusion: These results suggest that gene-environment interactions influence not only disadvantageous outcomes, but also sensitivity to features of the environment that could alleviate these outcomes.

    Funded by: NIMH NIH HHS: P50 MH062185, P50 MH062185-01, P50 MH062185-02, P50 MH062185-03, P50 MH062185-04, P50 MH062185-05, P50 MH062185-06, P50 MH062185-07, P50 MH062185-08, P50 MH062185-09, P50 MH062185-10, P50MH062185, R01 MH048514, R01 MH048514-08, R01 MH048514-09, R01 MH048514-10, R01 MH048514-11, R01 MH048514-12A1, R01 MH048514-13, R01 MH048514-14, R01 MH048514-15, R01 MH056390, R01 MH056390-06, R01 MH056390-07, R01 MH056390-07S1, R01 MH056390-08, R01 MH056390-09, R01 MH056390-10, R01 MH056390-11A2, R01 MH48514, R01MH056390

    Psychiatric genetics 2009;19;3;126-33

  • An association study of monoamine oxidase A (MAOA) gene polymorphism in methamphetamine psychosis.

    Nakamura K, Sekine Y, Takei N, Iwata Y, Suzuki K, Anitha A, Inada T, Harano M, Komiyama T, Yamada M, Iwata N, Iyo M, Sora I, Ozaki N, Ujike H and Mori N

    Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. nakamura@hama-med.ac.jp

    Methamphetamine continues to be the most widely abused drug in Japan. Chronic methamphetamine users show psychiatric signs, including methamphetamine psychosis. Monoamine oxidase A (MAOA) is one of the major enzymes responsible for the degradation of neurotransmitters. Abnormalities in MAO levels have been related to a wide range of psychiatric disorders. We examined whether or not the MAOA-u variable-number tandem repeat (VNTR) has a functional polymorphism in methamphetamine psychosis and whether or not such a polymorphism is related to the prolongation of psychosis. As expected, there was a significant difference in the MAOA-u VNTR between males with persistent versus transient methamphetamine psychosis (p=0.018, odds ratio (OR)=2.76, 95% CI: 1.18-6.46). Our results suggest that the high-activity allele class of MAOA-u VNTR in males may be involved in susceptibility to a persistent course of methamphetamine psychosis. We found no differences among females. The sample size of females with methamphetamine psychosis was too small to have significant analysis.

    Neuroscience letters 2009;455;2;120-3

  • Gene-gene interactions of CYP2A6 and MAOA polymorphisms on smoking behavior in Chinese male population.

    Tang X, Guo S, Sun H, Song X, Jiang Z, Sheng L, Zhou D, Hu Y and Chen D

    Department of Epidemiolgy and Biostatistics, Peking University Health Science Center, Peking, China.

    Objectives: Nicotine is the major psychoactive ingredient in tobacco, and is responsible for dependence through the nicotine-stimulated reward pathway mediated by the central dopaminergic system. Consequently, genetic polymorphisms in both nicotine metabolism and dopamine catabolism genes may influence smoking behavior, and interact with each other resulting in risk modulation. In this study, we investigated the association and multilocus gene-gene interactions of cytochrome P450 2A6 (CYP2A6), dopamine beta-hydroxylase (DBH), catechol O-methyl transferase (COMT), and monoamine oxidase A (MAOA) polymorphisms with smoking behavior in a community-based Chinese male population.

    Methods: The polymorphisms were genotyped in 203 current smokers, 66 former smokers, and 102 never smokers. Multivariate logistic regression models and the multifactor dimensionality reduction method were used to analyze the association and multilocus gene-gene interactions.

    Results: Statistically significant trends were shown for increased risk of smoking initiation in participants with CYP2A6*1B/CYP2A6*1B genotypes compared with those with CYP2A6*1A/CYP2A6*1A genotypes [odds ratio (OR)=3.5, 95% confidence interval (CI)= 1.5-8.1], and participants with CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking initiation (OR=2.4, 95% CI=1.2-4.5) and smoking persistence (OR=4.0, 95% CI=1.5-10.3) than those who have CYP2A6*4C genotypes. Moreover, the best model involved a gene-gene interaction between MAOA and CYP2A6 was characterized by the multifactor dimensionality reduction method (64.11% accuracy, P<0.001), and indicated that carriers of the combined 1460 T/O genotype for MAOA EcoRV and CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking (OR=15.4, 95% CI=4.5-52.5).

    Conclusion: These findings suggested a substantial influence of CYP2A6 polymorphism as well as the interaction with MAOA resulting in risk modulation on smoking behavior in Chinese male population.

    Pharmacogenetics and genomics 2009;19;5;345-52

  • Interactions between genotype and depressive symptoms on obesity.

    Fuemmeler BF, Agurs-Collins T, McClernon FJ, Kollins SH, Garrett ME and Ashley-Koch AE

    Duke University Medical Center, Durham, NC, USA. bernard.fuemmeler@duke.edu

    Depression and Genetic variation in serotonin and monoamine transmission have both been associated with body mass index (BMI), but their interaction effects are not well understood. We examined the interaction between depressive symptoms and functional polymorphisms of serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) on categories of BMI. Participants were from the National Longitudinal Study of Adolescent Health. Multiple logistic regression was used to investigate interactions between candidate genes and depression on risk of obesity (BMI > or = 30) or overweight + obese combined (BMI > or = 25). Males with an MAOA active allele with high depressive symptoms were at decreased risk of obesity (OR 0.22; 95% CI 0.06-0.78) and overweight + obesity (OR 0.48; 95% CI 0.26-0.89). No similar effect was observed among females. These findings highlight that the obesity-depression relationship may vary as a function of gender and genetic polymorphism, and suggest the need for further study.

    Funded by: NCI NIH HHS: K07 CA124905, K07 CA124905-04; NICHD NIH HHS: P01 HD031921; NIDA NIH HHS: K23 DA017261; NINDS NIH HHS: R01 NS049067

    Behavior genetics 2009;39;3;296-305

  • MAO-A and COMT genotypes as possible regulators of perinatal serotonergic symptoms after in utero exposure to SSRIs.

    Hilli J, Heikkinen T, Rontu R, Lehtimäki T, Kishida I, Aklillu E, Bertilsson L, Vahlberg T and Laine K

    Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland. johanna.hilli@utu.fi

    Intrauterine exposure to SSRIs in late pregnancy can cause various serotonergic symptoms in the newborns. We associated the severity of these symptoms to neurotransmitter concentrations and genetic polymorphisms in the cytochrome P450, MAO-A and COMT enzymes. Altogether 20 children with prenatal exposure to citalopram or fluoxetine were genotyped. Infants with two high-activity alleles of the MAO-A gene had significantly higher serotonergic symptom scores than infants with at least one low-activity allele (mean 8.8 vs. 2.4, p=0.024). These infants had also higher cord blood DHPG concentrations (p=0.0054). Carriers of the high-activity COMT alleles had higher cord blood prolactin concentrations (p=0.044). According to our results, the higher serotonergic symptom score and cord blood DHPG concentration in rapid MAO-A metabolizers suggest that norepinephrine may modify the severity of perinatal serotonergic symptoms. The COMT 1947G>A polymorphism may affect the occurrence of respiratory distress symptoms in infants with prenatal SSRI-exposure via a mechanism involving prolactin.

    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 2009;19;5;363-70

  • High-activity variants of the uMAOA polymorphism increase the risk for depression in a large primary care sample.

    Rivera M, Gutiérrez B, Molina E, Torres-González F, Bellón JA, Moreno-Küstner B, King M, Nazareth I, Martínez-González LJ, Martínez-Espín E, Muñoz-García MM, Motrico E, Martínez-Cañavate T, Lorente JA, Luna JD and Cervilla JA

    Sección de Psiquiatría e Instituto de Neurociencias, Universidad de Granada, Granada, Spain.

    Studies on the association between the functional uMAOA polymorphism and depression have yielded non-conclusive results up till now. One thousand two hundred twenty eight consecutive Spanish primary care attendees, participating in the PREDICT study, agreed to take part in this genetic PREDICT-Gene study. We explored the association between depression and either high-activity uMAOA alleles or genotypes. Depression was diagnosed using the Composite International Diagnostic Interview (CIDI) to establish three different depressive outcomes (ICD-10 Depressive Episode (DE), ICD-10 Severe Depressive Episode (SDE) and DSM-IV Major Depression (MD)). uMAOA genetic variation was determined by PCR amplification and subsequent electrophoresis. Crude and adjusted (gender and/or age) odds ratios, with 95% confidence intervals, were calculated for the associations between allele or genotype frequencies and all three depressive outcomes. We found associations between all three depressive phenotypes and either high-activity alleles or high-activity genotypes in both sexes. The associations were statistically significant for females but not for males. Testing the same associations on the entire sample (males and females) also yielded significant associations between depression and either high-activity alleles or high-activity genotype distribution that were independent of age and/or gender (ICD-10 DE: OR = 1.98; 95% CI: 1.42-1.77; P = 0.00002; ICD-10-SDE: OR = 2.05; 95% CI: 1.38-3.05; P = 0.0002; DSM-IV MD: OR = 1.91; 95% CI: (1.26-2.91); P = 0.0014). Our results provide fairly consistent evidence that high-activity variants of the MAOA promoter polymorphism confer a modestly higher risk for depression.

    Funded by: Medical Research Council: MC_U122797163

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;3;395-402

  • A common variant in DRD3 receptor is associated with autism spectrum disorder.

    de Krom M, Staal WG, Ophoff RA, Hendriks J, Buitelaar J, Franke B, de Jonge MV, Bolton P, Collier D, Curran S, van Engeland H and van Ree JM

    Department of Neuroscience and Pharmacology and Department of Child and Adolescent Psychiatry, Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.

    Background: The presence of specific and common genetic etiologies for autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) was investigated for 132 candidate genes in a two-stage design-association study.

    Methods: 1,536 single nucleotide polymorphisms (SNPs) covering these candidate genes were tested in ASD (n = 144) and ADHD (n = 110) patients and control subjects (n = 404) from The Netherlands. A second stage was performed with those SNPs from Stage I reaching a significance threshold for association of p < .01 in an independent sample of ASD patients (n = 128) and controls (n = 124) from the United Kingdom and a Dutch ADHD (n = 150) and control (n = 149) sample.

    Results: No shared association was found between ASD and ADHD. However, in the first and second ASD samples and in a joint statistical analysis, a significant association between SNP rs167771 located in the DRD3 gene was found (joint analysis uncorrected: p = 3.11 x 10(-6); corrected for multiple testing and potential stratification: p = .00162).

    Conclusions: The DRD3 gene is related to stereotyped behavior, liability to side effects of antipsychotic medication, and movement disorders and may therefore have important clinical implications for ASD.

    Biological psychiatry 2009;65;7;625-30

  • Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.

    Aklillu E, Karlsson S, Zachrisson OO, Ozdemir V and Agren H

    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden. Eleni.Aklillu@ki.se

    Objective: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy.

    Methods: In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF.

    Results: AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD.

    Conclusion: The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.

    Pharmacogenetics and genomics 2009;19;4;267-75

  • Monoamine oxidase A and childhood adversity as risk factors for conduct disorder in females.

    Prom-Wormley EC, Eaves LJ, Foley DL, Gardner CO, Archer KJ, Wormley BK, Maes HH, Riley BP and Silberg JL

    Department of Integrative Life Sciences, Virginia Commonwealth University 23298-0126, USA. ecprom@vcu.edu

    Background: Recent studies among males have reported a genotype-environment interaction (GxE) in which low-activity alleles at the monoamine oxidase A (MAOA) locus conferred greater sensitivity to the effects of childhood adversity on risk for conduct disorder (CD). So far, few studies of females have controlled for gene-environment correlation or used females heterozygous for this X-linked gene.

    Method: Logistic regression analysis of a sample of 721 females ages 8-17 years from the longitudinal Virginia Twin Study of Adolescent Behavioral Development (VTSABD) assessed the additive effects of MAOA genotypes on risk for CD, together with the main effect of childhood adversity and parental antisocial personality disorder (ASP), as well as the interaction of MAOA with childhood adversity on risk for CD.

    Results: A significant main effect of genotype on risk for CD was detected, where low-activity MAOA imparted the greatest risk to CD in girls while controlling for the significant effects of maternal ASP and childhood adversity. Significant GxE with weak effect was detected when environmental exposure was untransformed, indicating a higher sensitivity to childhood adversity in the presence of the high-activity MAOA allele. The interaction was no longer statistically significant after applying a ridit transformation to reflect the sample sizes exposed at each level of childhood adversity.

    Conclusions: The main effect of MAOA on risk for CD in females, its absence in males and directional difference of interaction is suggestive of genotype-sex interaction. As the effect of GxE on risk for CD was weak, its inclusion is not justified.

    Funded by: NIMH NIH HHS: MH-068521, MH-20030, MH-45268, R01 MH068521, T32 MH020030

    Psychological medicine 2009;39;4;579-90

  • Role of monoamine oxidases in the exaggerated 5-hydroxytryptamine-induced tension development of human isolated preeclamptic umbilical artery.

    Seto SW, Lam HY, Lau WS, Au AL, Lam TY, Chim SS, Ngai SM, Chan SW, Leung TY, Yeung JH, Kong SK, Leung GP, Lee SM and Kwan YW

    Department of Pharmacology, The Chinese University of Hong Kong, Hong Kong, PR China.

    We investigated the role(s) of monoamine oxidases (MAOs) on the altered 5-hydroxytryptamine (5-HT, serotonin)-induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women. An enhanced 5-HT-induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy. The enhanced component of 5-HT-induced tension development was eradicated by clorgyline (a MAO-A inhibitor). Blockade of eNOS (endothelial isoform nitric oxide synthase) (N(omega)-nitro-L-arginine methyl ester), 5-HT transporter (citalopram), 5-HT receptor subtypes (5HT2B, SB 204741; 5-HT2C, RS 102221; 5-HT7, SB 269970), and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5-HT-induced tension development as observed in the preeclamptic tissues. In contrast, no apparent changes in 5-HT-induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations. A decreased protein expression levels of MAO-A and eNOS (no iNOS and MAO-B expression was detected) and no change in caveolin-1 and 5-HT transporter expression were demonstrated in the umbilical artery (endothelium intact) lysate of preeclamptic pregnancy, compared to that of the umbilical artery of normal pregnancy. Thus, in the umbilical artery of preeclamptic pregnancy, a decrease of MAO-A and eNOS protein expression levels are probably associated with, or responsible for, the exaggerated 5-HT-induced tension development.

    European journal of pharmacology 2009;605;1-3;129-37

  • Effects of MAOA-genotype, alcohol consumption, and aging on violent behavior.

    Tikkanen R, Sjöberg RL, Ducci F, Goldman D, Holi M, Tiihonen J and Virkkunen M

    Institute of Clinical Medicine, Department of Psychiatry, University of Helsinki, Helsinki, Finland. roope.tikkanen@helsinki.fi

    Background: Environmental factors appear to interact with a functional polymorphism (MAOA-LPR) in the promoter region of the monoamine oxidase A gene (MAOA) in determining some forms of antisocial behavior. However, how MAOA-LPR modulates the effects of other factors such as alcohol consumption related to antisocial behavior is not completely understood.

    Methods: This study examines the conjunct effect of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. Recidivism in severe impulsive violent behavior was assessed after 7 to 15 years in a sample of 174 Finnish alcoholic offenders, the majority of whom exhibited antisocial or borderline personality disorder or both, and featured impulsive temperament traits.

    Results: The risk for committing new acts of violence increased by 2.3% for each kilogram of increase in yearly mean alcohol consumption (p = 0.004) and decreased by 7.3% for every year among offenders carrying the high activity MAOA genotype. In contrast, alcohol consumption and aging failed to affect violent behavior in the low activity MAOA genotyped offenders. MAOA-LPR showed no main effect on the risk for recidivistic violence.

    Conclusions: Violent offenders carrying the high activity MAOA genotype differ in several ways from carriers with the low activity MAOA risk allele previously associated with antisocial behavior. Finnish high activity MAOA genotyped risk alcoholics exhibiting antisocial behavior, high alcohol consumption, and abnormal alcohol-related impulsive and uncontrolled violence might represent an etiologically distinct alcohol dependence subtype.

    Funded by: Intramural NIH HHS: Z01 AA000306-02, Z99 OD999999

    Alcoholism, clinical and experimental research 2009;33;3;428-34

  • Family- and population-based association studies of monoamine oxidase A and autism spectrum disorders in Korean.

    Yoo HJ, Lee SK, Park M, Cho IH, Hyun SH, Lee JC, Yang SY and Kim SA

    Department of Psychiatry, Seoul National University Bundang Hospital, Kyunggi, Republic of Korea.

    Monoamine oxidase A gene (MAOA) has been thought to be a candidate gene implicated in autism spectrum disorder (ASD). This study evaluates the relationship between ASDs and MAOA markers (i.e., uVNTR and four single nucleotide polymorphisms (SNPs)) in 151 Korean family trios with children diagnosed with ASDs, and 193 unrelated Korean controls. The result of case-control global haplotype analysis also showed a statistically significant difference in haplotype frequencies between ASD patients and controls (male d.f.=5, p<0.001; female d.f.=7, p<0.001). With the specific haplotype analyses, the frequencies of the most frequent haplotype (AGG) with three SNPs (rs5906883+rs1137070+rs3027407) in ASD showed significant statistical differences between ASD patients and controls in both the male and female groups (d.f.=1, male p=0.001, female p<0.001). In a family-based association test (FBAT) analysis, it was observed that, in the dominant model, a three-repeat allele of a MAOA-uVNTR marker was preferentially transmitted in ASDs (Z=2.213, p=0.027). Moreover, in the global haplotype analysis, the statistically significant evidence of associations with ASD were demonstrated in additive and dominant models (additive chi(2)=11.349, d.f.=2, p=0.003; dominant chi(2)=6.198, d.f.=2, p=0.045).

    Neuroscience research 2009;63;3;172-6

  • Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation.

    McDermott R, Tingley D, Cowden J, Frazzetto G and Johnson DD

    Department of Political Science, Brown University, 36 Prospect Street, Providence, RI 02912, USA.

    Monoamine oxidase A gene (MAOA) has earned the nickname "warrior gene" because it has been linked to aggression in observational and survey-based studies. However, no controlled experimental studies have tested whether the warrior gene actually drives behavioral manifestations of these tendencies. We report an experiment, synthesizing work in psychology and behavioral economics, which demonstrates that aggression occurs with greater intensity and frequency as provocation is experimentally manipulated upwards, especially among low activity MAOA (MAOA-L) subjects. In this study, subjects paid to punish those they believed had taken money from them by administering varying amounts of unpleasantly hot (spicy) sauce to their opponent. There is some evidence of a main effect for genotype and some evidence for a gene by environment interaction, such that MAOA is less associated with the occurrence of aggression in a low provocation condition, but significantly predicts such behavior in a high provocation situation. This new evidence for genetic influences on aggression and punishment behavior complicates characterizations of humans as "altruistic" punishers and supports theories of cooperation that propose mixed strategies in the population. It also suggests important implications for the role of individual variance in genetic factors contributing to everyday behaviors and decisions.

    Proceedings of the National Academy of Sciences of the United States of America 2009;106;7;2118-23

  • Serotonin genes and gene-gene interactions in borderline personality disorder in a matched case-control study.

    Ni X, Chan D, Chan K, McMain S and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), 250 College Street, Toronto, Canada M5T1R8. xingqunni@hotmail.com

    Lines of evidence suggest serotonin genes are susceptibility candidates in borderline personality disorder (BPD). However, few molecular genetic studies on BPD have been reported, especially an overall lack of study on epistatic interactions. We genotyped 27 polymorphisms in 7 serotonin genes in 113 Caucasian BPD patients and matched (sex, age and ethnicity) controls. Program UNPHASED was used to perform association analyses for genotypes, alleles and haplotypes with a permutation test of 10,000 simulations. The Multifactor Dimensionality Reduction analysis was used to examine gene-gene interactions in serotonin system, including three other genes (5-HTT, 5-HT2A and MAOA) that we previously reported. Genotype and allele analyses showed that BPD significantly associated with 5-HT2C and TPH2. BPD patients had high frequencies of the 5-HT2C rs6318G allele (p=0.021) and G/G genotype (OR=2.25); and TPH2 rs2171363T allele (p=0.001) and T containing genotypes (OR=3.40). The 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3A and TPH1 showed no significant association with BPD for genotype, allele and haplotype analyses. We also detected significant interactions between 5-HT2C and TPH2 (p=0.001), and among 5-HT2C, 5-HTT, MAOA and TPH2 (p=0.001) in BPD. Patients with 5-HT2C rs6318G/G genotype had a high frequency of TPH2 rs2171363C/T genotype compared with controls. Our study indicates "that serotonin genes and their interactions may play a role in the susceptibility to borderline personality disorder.

    Progress in neuro-psychopharmacology & biological psychiatry 2009;33;1;128-33

  • Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis.

    Filonzi L, Magnani C, Lavezzi AM, Rindi G, Parmigiani S, Bevilacqua G, Matturri L and Marzano FN

    Department of Evolutionary and Functional Biology, University of Parma, Parma, Italy.

    Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

    Neurogenetics 2009;10;1;65-72

  • Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity.

    Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schöning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W and Suslow T

    Department of Psychiatry, University of Münster, Germany.

    The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

    The international journal of neuropsychopharmacology 2009;12;1;11-22

  • The genetics of Alzheimer's disease in Brazil: 10 years of analysis in a unique population.

    Oliveira JR, Nishimura AL, Lemos RR and Zatz M

    Department of Neuropsychiatry, Federal University of Pernambuco, Recife, PE, Brazil. joao.ricardo@ufpe.br

    Alzheimer's Disease (AD) is the most common type of dementia among the elderly, with devastating consequences for the patient, their relatives, and caregivers. More than 300 genetic polymorphisms have been involved with AD, demonstrating that this condition is polygenic and with a complex pattern of inheritance. This paper aims to report and compare the results of AD genetics studies in case-control and familial analysis performed in Brazil since our first publication, 10 years ago. They include the following genes/markers: Apolipoprotein E (APOE), 5-hidroxytryptamine transporter length polymorphic region (5-HTTLPR), brain-derived neurotrophin factor (BDNF), monoamine oxidase A (MAO-A), and two simple-sequence tandem repeat polymorphisms (DXS1047 and D10S1423). Previously unpublished data of the interleukin-1alpha (IL-1alpha) and interleukin-1 beta (IL-1beta) genes are reported here briefly. Results from others Brazilian studies with AD patients are also reported at this short review. Four local families studied with various markers at the chromosome 21, 19, 14, and 1 are briefly reported for the first time. The importance of studying DNA samples from Brazil is highlighted because of the uniqueness of its population, which presents both intense ethnical miscegenation, mainly at the east coast, but also clusters with high inbreeding rates in rural areas at the countryside. We discuss the current stage of extending these studies using high-throughput methods of large-scale genotyping, such as single nucleotide polymorphism microarrays, associated with bioinformatics tools that allow the analysis of such extensive number of genetics variables, with different levels of penetrance. There is still a long way between the huge amount of data gathered so far and the actual application toward the full understanding of AD, but the final goal is to develop precise tools for diagnosis and prognosis, creating new strategies for better treatments based on genetic profile.

    Journal of molecular neuroscience : MN 2009;37;1;74-9

  • Association of a monoamine oxidase-a gene promoter polymorphism with ADHD and anxiety in boys with autism spectrum disorder.

    Roohi J, DeVincent CJ, Hatchwell E and Gadow KD

    Department of Genetics, Stony Brook University, NY, USA.

    The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned comparisons indicated that children with the 4- versus 3-repeat allele had significantly (p < 05) more severe parent-rated ADHD inattention and impulsivity, and more severe teacher-rated symptoms of generalized anxiety. Our results support a growing body of research indicating that concomitant behavioral disturbances in children with ASD warrant consideration as clinical phenotypes, but replication with independent samples is necessary to confirm this preliminary finding.

    Funded by: NCRR NIH HHS: M01 RR010710, M01RR10710; NIGMS NIH HHS: T32 GM008444

    Journal of autism and developmental disorders 2009;39;1;67-74

  • No evidence for association between an MAOA functional polymorphism and susceptibility to Parkinson's disease.

    Williams-Gray C, Goris A, Foltynie T, Compston A, Sawcer S and Barker RA

    Funded by: Medical Research Council; Wellcome Trust

    Journal of neurology 2009;256;1;132-3

  • Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response.

    Peters EJ, Slager SL, Jenkins GD, Reinalda MS, Garriock HA, Shyn SI, Kraft JB, McGrath PJ and Hamilton SP

    Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA, USA.

    Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.

    Funded by: Howard Hughes Medical Institute; NCI NIH HHS: CA 94919, K07 CA094919; NIMH NIH HHS: MH 072802, N01 MH 90003, N01MH90003, R01 MH072802, R01 MH072802-04, R25 MH060482

    Pharmacogenetics and genomics 2009;19;1;1-10

  • Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population.

    Huang SY, Lin MT, Lin WW, Huang CC, Shy MJ and Lu RB

    Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan, ROC. hsy@ndmctsgh.edu.tw

    It has been proposed that an MAOA abnormality may be an important factor in the development of major depressive disorder (MDD). Various polymorphisms of the MAOA gene have been investigated for possible associations with mood disorders, but results have been inconsistent. The goal of the present study was to investigate whether polymorphisms of the MAOA gene are associated with MDD or alternatively with different clinical subgroups of MDD. A total of 590 Han Chinese subjects in Taiwan (312 controls and 278 MDD patients) were recruited. Among the males, there were no associations with MAOA polymorphisms. Among the females, an association was found between MAOA polymorphisms and severe MDD (P=0.041 for uVNTR and 0.017 for EcoRV (rs1137070), respectively). However, in analyses of haplotype frequencies and multiple logistic regression, MAOA polymorphisms were not associated with either MDD or its subgroups. The results suggest that MAOA polymorphisms do not play a major role in the pathogenesis of MDD or its subgroups. However, a potential role for a minor association with some specific subgroups and with different ethnic samples needs to be explored further.

    The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 2009;10;4 Pt 2;544-51

  • Genome-wide and candidate gene association study of cigarette smoking behaviors.

    Caporaso N, Gu F, Chatterjee N, Sheng-Chih J, Yu K, Yeager M, Chen C, Jacobs K, Wheeler W, Landi MT, Ziegler RG, Hunter DJ, Chanock S, Hankinson S, Kraft P and Bergen AW

    Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland, United States of America. caporaso@nih.gov

    The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, < or = 10 versus > 10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10(-7)) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10(-5) for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4x10(-5)), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up.

    Funded by: Intramural NIH HHS; NCI NIH HHS: P01 CA087969, T32 CA009547; NIDA NIH HHS: U01 DA020830

    PloS one 2009;4;2;e4653

  • Neighborhoods and genes and everything in between: understanding adolescent aggression in social and biological contexts.

    Hart D and Marmorstein NR

    Rutgers University, USA. daniel.hart@rutgers.edu

    Adolescent aggression was explored in relation to neighborhood and genetic characteristics. Child saturation (the proportion of the population consisting of children under the age of 15), ethnic heterogeneity, poverty, and urbanicity of neighborhoods were examined in relation to adolescent aggression in 12,098 adolescents followed longitudinally for 1 year. Longitudinal analyses indicated that child saturation was positively associated with increases in aggression, with this finding emerging among those living in the same neighborhood at both testing times and those who moved between testing times. In a subsample of males for whom genetic data were available, the relation of child saturation to adolescent aggression was moderated by the monoamine oxidase A (MAOA) gene. The regression of aggression on child saturation was steeper for those with the low activity version of the MAOA allele than among those with the high activity version of the allele. The implications of the results for an understanding of the origins and ontogeny of aggression and personality disorders are discussed.

    Funded by: NICHD NIH HHS: P01 HD031921; NIDA NIH HHS: K01 DA022456, K01 DA022456-03, K01DA022456

    Development and psychopathology 2009;21;3;961-73

  • Prolactin levels in olanzapine treatment correlate with positive symptoms of schizophrenia: results from an open-label, flexible-dose study.

    Chen YL, Cheng TS and Lung FW

    Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.

    Objective: This study was designed to investigate the relationship between the treatment effect of olanzapine and the serum prolactin level in schizophrenia and to investigate the factors that may act as predictors of response for olanzapine treatment.

    Method: Sixty patients who met the DSM-IV criteria for schizophrenia were included in the study. None of the patients were drug-naive, and they were given olanzapine in a flexible dose of 10-30 mg/day for 3 months after a 7-day drug washout period. Serum prolactin levels were measured at baseline (after drug washout) and at months 1, 2, and 3 during olanzapine treatment. A psychiatrist performed monthly ratings of symptoms using the Positive and Negative Syndrome Scale Manual (PANSS Manual). The Generalized Estimating Equations-I was used for data correlation analysis. Data were gathered from July 2005 to July 2006.

    Results: In general, the serum prolactin level was decreased in schizophrenia patients with olanzapine treatment, although the difference is not statistically significant (p = .974, p = .246, and p = .363 for the first, second, and third months, respectively). There was a close relationship between the improvement in positive symptoms and the change in serum prolactin levels before and after olanzapine treatment (p = .002). Moreover, the serum prolactin level also had a positive association with female gender (p = .008). The present study demonstrated no significant correlation between serum prolactin level, MAOA polymorphism, and DRD4 genotype.

    Conclusion: This finding suggests that the serum prolactin level may be a useful biological marker to predict the effectiveness of antipsychotics in schizophrenia.

    Primary care companion to the Journal of clinical psychiatry 2009;11;1;16-20

  • Association between monoamine oxidase A (MAOA) and personality traits in Japanese individuals.

    Tsuchimine S, Yasui-Furukori N, Kaneda A, Saito M, Nakagami T, Sato K and Kaneko S

    Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562 Japan.

    It has been reported that personality traits are related to several neurotransmitters. However, the association between personality traits and the central nervous system remains unclear. In the present study, we investigated the relationships between a polymorphism involving a variable number of tandem repeats in the promoter of the monoamine oxidase A (MAOA-VNTR) gene and personality traits, as assessed by the Temperament and Character Inventory (TCI). Promoter VNTRs in the MAOA were genotyped in 558 healthy Japanese individuals. Females homozygous for high-activity allele (4/4) had significantly higher persistence scores than those homozygous for the low-activity allele (3/3) (p=0.012, ANOVA). Meanwhile no difference in persistence was found between 3 and 4 allele in males. There were no differences between other scores of TCI subscales and MAOA-VNTR polymorphism. Our results suggest a gender-specific contribution of MAOA-VNTR polymorphism to persistence scores.

    Progress in neuro-psychopharmacology & biological psychiatry 2008;32;8;1932-5

  • Differential association between MAOA, ADHD and neuropsychological functioning in boys and girls.

    Rommelse NN, Altink ME, Arias-Vásquez A, Buschgens CJ, Fliers E, Faraone SV, Buitelaar JK, Sergeant JA, Oosterlaan J and Franke B

    Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, The Netherlands. n.lambregts-rommelse@psy.umcn.nl

    Attention-deficit/hyperactivity disorder (ADHD) is more common in boys than in girls. It has been hypothesized that this sex difference might be related to genes on the X-chromosome, like Monoamine Oxidase A (MAOA). Almost all studies on the role of MAOA in ADHD have focused predominantly on boys, making it unknown whether MAOA also has an effect on ADHD in girls, and few studies have investigated the relationship between MAOA and neuropsychological functioning, yet this may provide insight into the pathways leading from genotype to phenotype. The current study set out to examine the relationship between MAOA, ADHD, and neuropsychological functioning in both boys (265 boys with ADHD and 89 male non-affected siblings) and girls (85 girls with ADHD and 106 female non-affected siblings). A haplotype was used based on three single nucleotide polymorphisms (SNPs) (rs12843268, rs3027400, and rs1137070). Two haplotypes (GGC and ATT) captured 97% of the genetic variance in the investigated MAOA SNPs. The ATT haplotype was more common in non-affected siblings (P = 0.025), conferring a protective effect for ADHD in both boys and girls. The target and direction of the MAOA effect on neuropsychological functioning was different in boys and girls: The ATT haplotype was associated with poorer motor control in boys (P = 0.002), but with better visuo-spatial working memory in girls (P = 0.01). These findings suggest that the genetic and neuropsychological mechanisms underlying ADHD may be different in boys and girls and underline the importance of taking into account sex effects when studying ADHD.

    Funded by: NIMH NIH HHS: R01 MH62873-01A1

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;8;1524-30

  • Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study.

    Biederman J, Kim JW, Doyle AE, Mick E, Fagerness J, Smoller JW and Faraone SV

    Pediatric Psychopharmacology Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. jbiederman@partners.org

    A growing body of literature finds gender differences in ADHD. However, little is known about the causes of these differences. One possibility is that ADHD risk genes have sexually dimorphic effects. We have investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for which there is evidence of sexually dimorphic effects. Past neurobiological and genetic studies suggest that COMT, and SLC6A4 variants may have a greater influence on males and that SLC6A2, and MAOA variants may have a greater influence on females. Our results indicate that genetic associations are stronger when stratified by sex and in the same direction as the previous neurobiological studies indicate: associations were stronger in males for COMT, SLC6A4 and stronger in females for SLC6A2, MAOA. Moreover, we found a statistically significant gender effect in the case of COMT (P = 0.007) when we pooled our work with a prior study. In conclusion, we have found some evidence suggesting that the genetic association for these genes with ADHD may be influenced by the sex of the affected individual. Although our results are not fully validated yet, they should motivate further investigation of gender effects in ADHD genetic association studies.

    Funded by: NICHD NIH HHS: R01 HD037694, R01 HD037694-05, R01 HD037999, R01HD37694, R01HD37999; NIMH NIH HHS: R01 MH066877, R01MH66877

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;8;1511-8

  • Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers.

    Maron E, Tõru I, Tasa G, Must A, Toover E, Lang A, Vasar V and Shlik J

    Department of Psychiatry, University of Tartu, Tartu, Estonia. Eduard.Maron@kliinikum.ee

    Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 +/- 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A -1019C-G, 5-HTR2A 102T-C, CCKR1 246G-A, CCKR2 -215C-A, DRD1 -94G-A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.

    Neuroscience letters 2008;446;2-3;88-92

  • Polymorphisms in mitochondrial genes and prostate cancer risk.

    Wang L, McDonnell SK, Hebbring SJ, Cunningham JM, St Sauver J, Cerhan JR, Isaya G, Schaid DJ and Thibodeau SN

    Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA.

    The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and implicated in many diseases, including cancer. To evaluate whether mitochondria-related genes are associated with increased risk for prostate cancer, we genotyped 24 single-nucleotide polymorphisms (SNP) within the mitochondrial genome and 376 tagSNPs localized to 78 nuclear-encoded mitochondrial genes. The tagSNPs were selected to achieve > or = 80% coverage based on linkage disequilibrium. We compared allele and haplotype frequencies in approximately 1,000 prostate cancer cases with approximately 500 population controls. An association with prostate cancer was not detected for any of the SNPs within the mitochondrial genome individually or for 10 mitochondrial common haplotypes when evaluated using a global score statistic. For the nuclear-encoded genes, none of the tagSNPs were significantly associated with prostate cancer after adjusting for multiple testing. Nonetheless, we evaluated unadjusted P values by comparing our results with those from the Cancer Genetic Markers of Susceptibility (CGEMS) phase I data set. Seven tagSNPs had unadjusted P < or = 0.05 in both our data and in CGEMS (two SNPs were identical and five were in strong linkage disequilibrium with CGEMS SNPs). These seven SNPs (rs17184211, rs4147684, rs4233367, rs2070902, rs3829037, rs7830235, and rs1203213) are located in genes MTRR, NDUFA9, NDUFS2, NDUFB9, and COX7A2, respectively. Five of the seven SNPs were further included in the CGEMS phase II study; however, none of the findings for these were replicated. Overall, these results suggest that polymorphisms in the mitochondrial genome and those in the nuclear-encoded mitochondrial genes evaluated are not substantial risk factors for prostate cancer.

    Funded by: NCI NIH HHS: CA91956, P50 CA091956, P50 CA091956-020001

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2008;17;12;3558-66

  • Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism.

    Gokturk C, Schultze S, Nilsson KW, von Knorring L, Oreland L and Hallman J

    Department of Neuroscience, Pharmacology, Uppsala University, Uppsala, Sweden.

    The serotonin system is known to play a pivotal role for mood, behaviour and psychic illness as e.g. alcoholism. Alcoholism in both males and females has been associated with polymorphisms in genes encoding for proteins of importance for central serotonergic function. Genotyping of two functional polymorphisms in the promoter region of the serotonin transporter and monoamine oxidase-A, respectively, (5-HTT-LPR and MAOA-VNTR), was performed in a group of women with severe alcohol addiction. A large sample of adolescent females from a normal population was used as controls. A significantly higher frequency of the LL 5-HTT genotype (high activity) was found in female addicts without a known co-morbid psychiatric disorder than in the controls. Genotype of the MAOA-VNTR polymorphism did not differ significantly between addicts and controls. However, within the group of alcoholics, when the patients with known co-morbid psychiatric disorders were excluded, aggressive anti-social behaviour was significantly linked to the presence of the high activity MAOA allele. The pattern of associations between genotypes of 5-HTT-LPR and MAOA-VNTR in women with severe alcoholism differs from most corresponding studies on males.

    Archives of women's mental health 2008;11;5-6;347-55

  • Relationship of genetic variability and depressive symptoms to adverse events after coronary artery bypass graft surgery.

    Phillips-Bute B, Mathew JP, Blumenthal JA, Morris RW, Podgoreanu MV, Smith M, Stafford-Smith M, Grocott HP, Schwinn DA, Newman MF and Perioperative Genetics and Safety Outcomes Investigative Team

    Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. phill016@mc.duke.edu

    Objective: To assess genetic variability in two serotonin-related gene polymorphisms (MAOA-uVNTR and 5HTTLPR) and their relationships to depression and adverse cardiac events in a sample of patients undergoing coronary artery bypass surgery.

    Methods: A total of 427 coronary artery bypass graft (CABG) patients were genotyped for two polymorphisms and assessed for depressive symptoms at three time points, in accordance with the Center for Epidemiological Studies-Depression (CES-D): preoperative baseline; 6 months postoperative; and 1 year postoperative. Logistic regression was used to assess the association between depressive symptoms (CES-D = >16), genotype differences, and cardiac events. Because MAOA-uVNTR is sex-linked, males and females were analyzed separately for this polymorphism; sexes were combined for the 5HTTLPR analysis.

    Results: Depressed patients were more likely than nondepressed patients to have a new cardiac event within 2 years of surgery (p < .0001); depressed patients who carry the long (L) allele of the 5HTTLPR polymorphism were more likely than the short/short (S/S carriers to have an event (p = .0002). Genetic associations with 6-month and 1-year postoperative depressive symptoms do not survive adjustment for baseline depressive symptoms.

    Conclusions: A serotonin-related gene polymorphism--5HTTLPR--was associated with adverse cardiac events post CABG, in combination with depressive symptoms. Because depressed patients with the L allele of the 5HTTLPR polymorphism were more likely to have an event compared with the S/S carriers, combining genetic and psychiatric profiling may prove useful in identifying patients at the highest risk for adverse outcomes post CABG.

    Funded by: NCRR NIH HHS: M01 RR000030-43, M01 RR000030-44, M01 RR000030-45, M01-RR-30; NHLBI NIH HHS: HL075273, HL54316, R01 HL075273, R01 HL075273-03; NIA NIH HHS: AG09663, R01 AG009663, R01 AG009663-12, R01 AG009663-13

    Psychosomatic medicine 2008;70;9;953-9

  • Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.

    Mickey BJ, Ducci F, Hodgkinson CA, Langenecker SA, Goldman D and Zubieta JK

    Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109-0720, USA.

    The serotonergic system, including the serotonin 1A (5-HT(1A)) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT(1A) receptor expression. We used positron emission tomography and [(11)C]WAY-100635 to quantify 5-HT(1A) receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT(1A) receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT(1A) receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT(1A) receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.

    Funded by: Intramural NIH HHS: Z01 AA000306-02; NCRR NIH HHS: M01 RR000042, M01 RR000042-441387, M01 RR000042-441440, RR00042; NIMH NIH HHS: P01 MH042251, P01 MH042251-160013, P01 MH42251, R25 MH6374

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28;44;11354-9

  • Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene.

    Davis LK, Hazlett HC, Librant AL, Nopoulos P, Sheffield VC, Piven J and Wassink TH

    Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. lea-davis@uiowa.edu

    Monoamine oxidase A (MAOA) is an enzyme expressed in the brain that metabolizes dopamine, norepinephrine, epinephrine, and serotonin. Abnormalities of serotonin neurotransmission have long been implicated in the psychopathology of autism. A polymorphism exists within the promoter region of the MAOA gene that influences MAOA expression levels so that "low activity" alleles are associated with increased neurotransmitter levels in the brain. Individuals with autism often exhibit elevated serotonin levels. Additional studies indicate that the "low activity" allele may be associated with lower IQ and more severe autistic symptoms. In this study we genotyped the MAOA promoter polymorphism in a group of 29 males (age 2-3 years) with autism and a group of 39 healthy pediatric controls for whom brain MRI data was available. We found a consistent association between the "low activity" allele and larger brain volumes for regions of the cortex in children with autism but not in controls. We did not find evidence for over-transmission of the "low activity" allele in a separate sample of 114 affected sib pair families. Nor did we find any unknown SNPs in yet another sample of 96 probands. Future studies will determine if there is a more severe clinical phenotype associated with both the "low activity" genotype and the larger brain volumes in our sample.

    Funded by: NICHD NIH HHS: HD03110, P30 HD003110, P30 HD003110-42; NIGMS NIH HHS: T32 GM008629, T32 GM008629-11; NIMH NIH HHS: MH066418, MH61696, R01 MH061696, R01 MH061696-05, U54 MH066418, U54 MH066418-05

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;7;1145-51

  • Worldwide genetic variation in dopamine and serotonin pathway genes: implications for association studies.

    Gardner M, Bertranpetit J and Comas D

    Unitat de Biologia Evolutiva, Universitat Pompeu Fabra, Doctor Aiguader, Barcelona, Spain.

    The dopamine and serotonin systems are two of the most important neurotransmitter pathways in the human nervous system and their roles in controlling behavior and mental status are well accepted. Genes from both systems have been widely implicated in psychiatric and behavioral disorders, with numerous reports of associations and almost equally as numerous reports of the failure to replicate a previous finding of association. We investigate a set of 21 dopamine and serotonin genes commonly tested for association with psychiatric disease in a set of 39 worldwide populations representing global genetic diversity to see whether the failure to replicate findings of association may be explained by population based differences in allele frequencies and linkage disequilibrium (LD) in this gene set. We present results demonstrating a surprising homogeneity of the allele frequencies across worldwide populations in these genes. LD both for populations within continent groupings and across continental regions also showed a remarkable similarity. These findings taken together suggest that ethnic differences in these parameters are not major generators of artifacts in genetic association studies of psychiatric disorders with genes from this set. Therefore, factors other than ethnic differences in genetic variation may explain the discrepancies reported among genetic association studies with this set of genes to date. The transferability of tagSNPs defined in the HapMap populations to other worldwide populations was also investigated and found to be high. A list of tagSNPs per gene and continental region is proposed providing a guide for future association studies with these genes.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;7;1070-5

  • 5-HT2C receptor and MAO-A interaction analysis: no association with suicidal behaviour in bipolar patients.

    De Luca V, Tharmaligam S, Strauss J and Kennedy JL

    Dept. of Psychiatry, University of Toronto, 250 College Street, R-30, Toronto (ON), Canada M5T 1R8. vincenzo_deluca@camh.net

    The serotonin 2C (HTR2C) receptor has been implicated in suicide-related behaviours, however there are not many studies to date about HTR2C and suicidality. We studied HTR2C haplotypes in suicide attempters, where our sample composed of 306 families with at least one member affected by bipolar disorder. HTR2C (Cys23Ser and a common STR in the promoter) variants were analyzed with respect to attempter status and the severity of suicidal behaviour. The X-linked haplotype analysis in relation to suicide attempt did not reveal any significant association. Furthermore, we performed a particular gene-gene interaction for the X-linked serotonergic genes (HTR2C and MAOA), and found no association among this intergenic haplotype combination and suicidal behaviour in bipolar disorder.

    European archives of psychiatry and clinical neuroscience 2008;258;7;428-33

  • HPA axis function in male caregivers: effect of the monoamine oxidase-A gene promoter (MAOA-uVNTR).

    Brummett BH, Boyle SH, Siegler IC, Kuhn CM, Surwit RS, Garrett ME, Collins A, Ashley-Koch A and Williams RB

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. brummett@duke.edu

    Caregiving stress is associated with negative health outcomes. Neuroendocrine functioning may be a mediator of such outcomes. The MAOA gene regulates activity of neurotransmitters involved with neuroendocrine responses to stress. Differences in polymorphisms of this gene have been shown to influence susceptibility to stress. Therefore, we examined allelic variation in MAOA-uVNTR, a functional polymorphism of MAOA, as a moderator of chronic stress effects on urinary cortisol excretion in 74 males enrolled in a case/control study of caregivers for relatives with dementia. Mixed models analysis of variance were used to examine MAOA-uVNTR genotype (3 repeats vs. 3.5/4 repeats) as a moderator of the impact of stress (caregiver vs. non-caregiver) on the urinary excretion pattern (overnight, daytime, evening) of cortisol. Caregivers with MAOA-uVNTR alleles associated with less transcriptional activity (3-repeats) displayed a pattern of cortisol excretion -- a decrease from overnight to daytime -- that was suggestive of HPA axis blunting, as compared to non-caregivers and those caregivers with the more active alleles (3.5/4 repeats) (cortisol p<.043). Individuals with less active MAOA-uVNTR alleles who are under chronic stress may be at increased risk for exhaustion of the HPA response to such stress.

    Funded by: NCRR NIH HHS: M01 RR30L; NHLBI NIH HHS: 3P01 HL036587, P01 HL036587, P01 HL036587-19; NIA NIH HHS: P30 AG028716, R01 AG019605, R01 AG019605-04, R01 AG19605; NIMH NIH HHS: R01 MH057663, R01 MH57663

    Biological psychology 2008;79;2;250-5

  • Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.

    Hosgood HD, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, He X, Chatterjee N, Caporaso NE, Zhu Y, Chanock SJ, Zheng T and Lan Q

    Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. hosgoodd@mail.nih.gov

    Common genetic variation may play an important role in altering lung cancer risk. We conducted a pathway-based candidate gene evaluation to identify genetic variations that may be associated with lung cancer in a population-based case-control study in Xuan Wei, China (122 cases and 111 controls). A total of 1260 single-nucleotide polymorphisms (SNPs) in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of 10 pathways based on gene ontology. Logistic regression was used to assess the marginal effect of each SNP on lung cancer susceptibility. The minP test was used to identify statistically significant associations at the gene level. Important pathways were identified using a test of proportions and the rank truncated product methods. The cell cycle pathway was found as the most important pathway (P = 0.044) with four genes significantly associated with lung cancer (PLA2G6 minP = 0.001, CCNA2 minP = 0.006, GSK3 beta minP = 0.007 and EGF minP = 0.013), after adjusting for multiple comparisons. Interestingly, most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival, and may be important in lung cancer etiology in Xuan Wei. These results should be viewed as exploratory until they are replicated in a larger study.

    Funded by: Intramural NIH HHS; NCI NIH HHS: TU2 CA105666

    Carcinogenesis 2008;29;10;1938-43

  • Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells.

    Zhao H, Nolley R, Chen Z, Reese SW and Peehl DM

    Department of Urology Stanford University School of Medicine 300 Pasteur Drive, Grant Building S227 MC 5118, Stanford, CA 94305, USA.

    Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiation-promoting conditions, clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.

    Funded by: NCI NIH HHS: CA121460, CA123532, K01 CA123532, K01 CA123532-02, K01 CA123532-03, R01 CA121460, R01 CA121460-03

    Differentiation; research in biological diversity 2008;76;7;820-30

  • Neither single-marker nor haplotype analyses support an association between monoamine oxidase A gene and bipolar disorder.

    Huang SY, Lin MT, Shy MJ, Lin WW, Lin FY and Lu RB

    Department of Psychiatry, National Defense Medical Center, Tri-Service General Hospital, No. 325, Cheng-Kung Road, Sec. 2, Nei-Hu District, Taipei, 114, Taiwan. hsy@ndmctsgh.edu.tw

    Monoamine oxidase A (MAOA) abnormality has been suggested as a crucial factor in the pathogenesis of mood disorder, because MAOA is associated with the metabolism of monoamines such as serotonin and norepinephrine. Various MAOA gene polymorphisms have been investigated for possible associations with bipolar disorder (BD), but the results are controversial. Our goal was to investigate whether MAOA gene polymorphisms, especially the promoter uVNTR polymorphism and the EcoRV polymorphism, are associated either with BD or with different clinical subtypes of BD. A total of 714 Han Chinese subjects in Taiwan (305 controls and 409 BD patients) were recruited for study. All subjects were interviewed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime; BD was diagnosed according to DSM-IV criteria. Genotyping for MAOA polymorphisms was performed using PCR and restriction fragment length polymorphism. The MAOA promoter polymorphisms uVNTR and EcoRV were not associated with BD or any of its subtypes, in either the frequencies of alleles or genotypes. In multiple logistic regression and haplotype frequency analysis, we confirmed these negative results in both females and males. Our results suggest that MAOA polymorphisms do not play a major role in pathogenesis of BD or its clinical subtypes in Han Chinese.

    European archives of psychiatry and clinical neuroscience 2008;258;6;350-6

  • MAO A VNTR polymorphism and variation in human morphology: a VBM study.

    Cerasa A, Gioia MC, Labate A, Lanza P, Magariello A, Muglia M and Quattrone A

    Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy. a.cerasa@isn.cnr.it

    The X-linked monoamine oxidase A (MAO A) gene, coding for an enzyme especially involved in the serotonin catabolism, presents a well-characterized functional polymorphism (long and short variants) in the promoter region that alters the transcriptional activity of the gene and hence the function of the corresponding proteins. Using optimized voxel-based morphometry, we studied the effect of this functional polymorphism on brain morphology in normal individuals. Fifty-nine male healthy individuals (33 MAO A-high and 26 MAO A-low) were investigated. Voxel-based morphometry showed that the carriers of the long variant were significantly associated with loss of grey matter in orbitofrontal cortex, bilaterally. This study reveals pronounced genotype-related structural changes in a specific prefrontal region previously observed to mediate neurofunctional responses in behavioral tasks.

    Neuroreport 2008;19;11;1107-10

  • MAOA methylation is associated with nicotine and alcohol dependence in women.

    Philibert RA, Gunter TD, Beach SR, Brody GH and Madan A

    Department of Psychiatry, The University of Iowa, Iowa City, Iowa, USA. robert-philibert@uiowa.edu

    In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the monoamine oxidase A (MAOA) locus. In order to examine the role of methylation at this locus, we performed quantitative methylation analysis across the promoter region of this gene in lymphoblast lines derived from 191 subjects participating in the Iowa Adoption Studies (IAS). We analyzed the resulting data with respect to genotype and lifetime symptom counts for the more common major behavioral disorders in the IAS, antisocial personality disorder (ASPD), and substance use disorders (alcohol (AD) and nicotine dependence (ND)). We found that methylation status was significantly associated with lifetime symptom counts for ND (P < 0.001) and AD (P < 0.008) in women, but not men. Furthermore, a trend was found for women homozygous for the 3,3 allele to have a higher degree of overall methylation than women homozygous for the 4,4 allele (P < 0.10). We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order.

    Funded by: NIDA NIH HHS: DA 015789, R01 DA015789

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;5;565-70

  • A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A).

    Shiels MS, Huang HY, Hoffman SC, Shugart YY, Bolton JH, Platz EA, Helzlsouer KJ and Alberg AJ

    Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

    Objective: Cigarette smoking behavior may be influenced by catechol-O-methlyltransferase (COMT), dopamine beta-hydroxylase (DBH), and monamine oxidase-A (MAO-A), genes that play roles in dopamine metabolism. The association between common polymorphisms of these genes and smoking behavior was assessed among 10,059 Caucasian volunteers in Washington County, MD in 1989.

    Methods: Age-adjusted logistic regression was used to measure the association between variants of these single nucleotide polymorphisms and smoking initiation and persistent smoking.

    Results: Overall, no association was seen between each genotype and smoking behavior. However, among younger (<54 years) women, the COMT GG genotype was positively associated with smoking initiation (OR=1.3; 95% CI: 1.0 1.5), and the MAO-A TT genotype was inversely associated with persistent smoking (OR=0.7; 95% CI: 0.4, 1.0). Men who smoked fewer than 10 cigarettes per day were more likely to be persistent smokers if they had the COMT GG (OR=1.7; 95% CI: 1.0, 2.9) or the DBH GG (OR=1.6; 95% CI: 1.0, 2.5) genotypes.

    Conclusion: Overall the results of this large community-based study do not provide evidence to support the presence of important associations between variants of COMT, DBH, or MAO-A and smoking initiation or persistent smoking.

    Funded by: NCI NIH HHS: CA105069, P30 CA138313, R01 CA105069, R01 CA105069-02, T32 CA009314, T32 CA009314-23, T32 CA009314-28S3; NIA NIH HHS: 5U01AG018033, U01 AG018033, U01 AG018033-04

    Preventive medicine 2008;47;1;116-22

  • The functional MAOA-uVNTR promoter polymorphism in patients with frontotemporal dementia.

    Reif A, Scarpini E, Venturelli E, Töpner T, Fenoglio C, Lesch KP and Galimberti D

    Department of Psychiatry and Psychotherapy, Section of Clinical and Molecular Psychobiology, University of Würzburg, Würzburg, Germany. a.reif@gmx.net

    The genetic underpinnings of frontotemporal dementia (FTD), a rare yet early onset disorder still remains elusive. As FTD is characterized by a serotonergic deficit in the frontal lobe, and as some symptoms of FTD resemble conditions of monoamino oxidase A (MAO-A) deficiency, MAO-A is an attractive candidate gene for case-control association studies of FTD. We have thus ascertained 62 Italian FTD patients and 151 controls matched to age and genotyped them for a functional promoter polymorphism, termed MAOA-uVNTR. However, no significant differences were observed between patients and controls. Bearing in mind the caveat of the small patient sample size, our data nevertheless argue against a major genetic role of MAO-A polymorphism in FTD.

    European journal of neurology 2008;15;6;637-9

  • Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome.

    Nonnis Marzano F, Maldini M, Filonzi L, Lavezzi AM, Parmigiani S, Magnani C, Bevilacqua G and Matturri L

    Department of Evolutionary and Functional Biology, University of Parma, 43100 Parma, Italy. francesco.nonnismarzano@unipr.it

    Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.

    Genomics 2008;91;6;485-91

  • Association analysis of monoamine oxidase A gene and bipolar affective disorder in Han Chinese.

    Lin YM, Davamani F, Yang WC, Lai TJ and Sun HS

    Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan. hssun@mail.ncku.edu.tw.

    Background: Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in degrading several different biological amines, including serotonin. Although several pieces of evidence suggested that MAOA is important in the etiology of bipolar affective disorder (BPD), associations for markers of the MAOA gene with BPD were not conclusive and the association has not been investigated in Taiwanese population. This study was designed to illustrate the role of MAOA in the etiology of BPD in Han Chinese.

    Methods: Two markers, a dinucleotide polymorphism in exon 2 and a functional uVNTR on the promoter of the MAOA gene, were used to study the genetic association in 108 unrelated patients with BPD and 103 healthy controls. Allelic distributions of two polymorphisms were analyzed and, caused the MAOA located at X chromosome, haplotype association was performed using haplotype unambiguously assigned in male participants.

    Results: While no difference in allelic distributions of two MAOA polymorphisms was found, the risk haplotype 114S was associated with BPD in male patients (P = 0.03). The significance, however, was not found in female patients with 114S haplotype.

    Conclusion: Results from this study suggest that MAOA may have a gender-specific and small effect on the etiology of BPD in Taiwan. Due to the limited sample size, results from this study need to be confirmed in replicates.

    Behavioral and brain functions : BBF 2008;4;21

  • Brain monoamine oxidase A activity predicts trait aggression.

    Alia-Klein N, Goldstein RZ, Kriplani A, Logan J, Tomasi D, Williams B, Telang F, Shumay E, Biegon A, Craig IW, Henn F, Wang GJ, Volkow ND and Fowler JS

    Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA. nellyklein@bnl.gov

    The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

    Funded by: NCRR NIH HHS: M01 RR010710, MO1RR10710; NIDA NIH HHS: K05 DA020001, K05DA020001, L30 DA018402-01, L30 DA018402-02

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28;19;5099-104

  • The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity.

    Guo G, Ou XM, Roettger M and Shih JC

    Department of Sociology, Carolina Center for Genome Sciences, Carolina Population Center, University of North Carolina - Chapel Hill, Chapel Hill, NC 27599-3210, USA. guang_guo@unc.edu

    Genetic studies of delinquent and criminal behavior are rare in spite of the wide recognition that individuals may differ in their propensity for delinquency and criminality. Using 2524 participants in Add Health in the United States, the present study demonstrates a link between the rare 2 repeat of the 30-bp VNTR in the MAOA gene and much higher levels of self-reported serious and violent delinquency. The evidence is based on a statistical association analysis and a functional analysis of MAOA promoter activity using two human brain-derived cell lines: neuroblastoma SH-SY5Y and human glioblastoma 1242-MG. The association analysis shows that men with a 2R report a level of serious delinquency and violent delinquency in adolescence and young adulthood that were about twice (CI: (0.21, 3.24), P=0.025; and CI: (0.37, 2.5), P=0.008 for serious and violent delinquency, respectively) as high as those for participants with the other variants. The results for women are similar, but weaker. In the functional analysis, the 2 repeat exhibits much lower levels of promoter activity than the 3 or 4 repeat.

    Funded by: NICHD NIH HHS: HD031921-050005, HD042490-02, HD053385-01, P01 HD031921, P01 HD031921-050005, P01-HD31921, R03 HD042490, R03 HD042490-02, R03 HD053385, R03 HD053385-01, R24 HD050924

    European journal of human genetics : EJHG 2008;16;5;626-34

  • ADHD and Disruptive Behavior scores - associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents.

    Malmberg K, Wargelius HL, Lichtenstein P, Oreland L and Larsson JO

    Karolinska Institutet, Department of Woman and Child Health, Child and Adolescent Psychiatric Unit Q3:04, Astrid Lindgren Children's Hospital, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. kerstin.malmberg@ki.se

    Background: Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorder (DBD). We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B) activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR) and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR).

    Methods: A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes.

    Results: We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD). In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD). In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior.

    Conclusion: Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.

    BMC psychiatry 2008;8;28

  • Genetically dependent modulation of serotonergic inactivation in the human prefrontal cortex.

    Passamonti L, Cerasa A, Gioia MC, Magariello A, Muglia M, Quattrone A and Fera F

    Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, 87050, Italy.

    Previous research suggests that genetic variations regulating serotonergic neurotransmission mediate individual differences in the neural network underlying impulsive and aggressive behaviour. Although with conflicting findings, the monoamine oxidase-A (MAOA) and the serotonin transporter (5HTT) gene polymorphisms have been associated with an increased risk to develop impulsive and aggressive behaviour. Double knock-out mice studies have also demonstrated that MAOA and 5HTT genes strongly interact in the metabolic pathway leading to the serotonergic inactivation; however, their potential interactive effect in human brain remains uninvestigated. We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to assess the independent and interactive effects of both MAOA and 5HTT polymorphisms on the brain activity elicited by a response inhibition task in healthy volunteers. Multivariate analysis demonstrated an individual effect of both MAOA and 5HTT polymorphisms and a strong allele-allele interaction in the anterior cingulate cortex (ACC), a key region implicated in cognitive control and in the pathophysiology of impulsive and aggressive behaviour. These findings suggest that the MAOAx5HTT allelic interaction exerts a significant modulation on the BOLD response associated with response inhibition and contribute to validate haplotype models as useful tools for a better understanding of the neurobiology underlying complex cognitive functions.

    NeuroImage 2008;40;3;1264-73

  • Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors.

    Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E and Tsukihara T

    Laboratory of Protein Crystallography, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.

    The mitochondrial outer membrane-anchored monoamine oxidase (MAO) is a biochemically important flavoenzyme that catalyzes the deamination of biogenic and xenobiotic amines. Its two subtypes, MAOA and MAOB, are linked to several psychiatric disorders and therefore are interesting targets for drug design. To understand the relationship between structure and function of this enzyme, we extended our previous low-resolution rat MAOA structure to the high-resolution wild-type and G110A mutant human MAOA structures at 2.2 and 2.17 A, respectively. The high-resolution MAOA structures are similar to those of rat MAOA and human MAOB, but different from the known structure of human MAOA [De Colibus L, et al. (2005) Proc Natl Acad Sci USA 102:12684-12689], specifically regarding residues 108-118 and 210-216, which surround the substrate/inhibitor cavity. The results confirm that the inhibitor selectivity of MAOA and MAOB is caused by the structural differences arising from Ile-335 in MAOA vs. Tyr-326 in MAOB. The structures exhibit a C-terminal transmembrane helix with clear electron density, as is also seen in rat MAOA. Mutations on one residue of loop 108-118, G110, which is far from the active center but close to the membrane surface, cause the solubilized enzyme to undergo a dramatic drop in activity, but have less effect when the enzyme is anchored in the membrane. These results suggest that the flexibility of loop 108-118, facilitated by anchoring the enzyme into the membrane, is essential for controlling substrate access to the active site. We report on the observation of the structure-function relationship between a transmembrane helical anchor and an extra-membrane domain.

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;15;5739-44

  • Ventro-lateral prefrontal activity during working memory is modulated by MAO A genetic variation.

    Cerasa A, Gioia MC, Fera F, Passamonti L, Liguori M, Lanza P, Muglia M, Magariello A and Quattrone A

    Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy. a.cerasa@isn.cnr.it

    Several lines of evidence have highlighted the role of the serotonergic system in working memory (WM) processes. The X-linked Mono-Amine Oxidase A (MAO A) gene, coding for an enzyme especially involved in the serotonin (5-HT) catabolism, presents a well-characterized functional polymorphism consisting in a variable number of tandem repeats (VNTR) in the promoter region with high activity and low activity variants. The high activity allele carriers have been associated with higher enzyme expression, lower amine concentration and altered prefrontal cortex (PFC) function during motor inhibition, but a direct effect of MAO A genotype on WM-related brain activity has not been demonstrated. We have studied the relationship of this polymorphism to brain activity elicited by a spatial working memory task (n-back) using blood oxygenation level-dependent functional magnetic resonance imaging in 30 healthy male individuals matched for a series of demographic and genetic variables (COMT Val108/158Met). We show that the high activity allele was significantly (p-level<0,001) associated with increased activity of the right ventro-lateral PFC (VLPFC, BA 47) during the high load condition of the n-back task. Our data reveal pronounced genotype-related functional changes in specific prefrontal region (VLPFC) subserving spatial working memory. Moreover, given the well-known role of this area in inhibitory control, our finding also provides new evidence for the involvement of 5-HT in PFC-mediated WM function.

    Brain research 2008;1201;114-21

  • Monoamine oxidase A-uVNTR genotype affects limbic brain activity in response to affective facial stimuli.

    Lee BT and Ham BJ

    Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

    Monoamine oxidase A (MAOA) enzymatically degrades biogenic amines such as norepinephrine, dopamine, and serotonin, and plays a key role in the regulation of their neurotransmission. Allelic variations at the MAOA locus have been implicated in the neurobiology of aggression and impulsivity. We investigated the possible relationship between the MAOA-upstream variable number of tandem repeats (uVNTR) polymorphism and brain responses to negative facial stimuli, using functional magnetic resonance imaging (fMRI). We found a significant association between a low activity allele of MAOA-uVNTR and neural activation to negative facial stimuli. In the sad condition, participants with the low activity allele showed greater brain activity in the left amygdala. In the angry condition, participants with the low activity allele showed greater brain activity in the right anterior cingulate cortex and hippocampus. Our results suggest that MAOA-uVNTR polymorphism can affect activation of limbic regions, elicited by negative emotional stimuli.

    Neuroreport 2008;19;5;515-9

  • Meta-study on association between the monoamine oxidase A gene (MAOA) and schizophrenia.

    Li D and He L

    Bio-X Center, Shanghai Jiao Tong University, Shanghai, China. dli@rockefeller.edu

    The human monoamine oxidase A gene (MAOA) has attracted considerable attention as a candidate gene for schizophrenia based both on its chromosomal position and its enzyme function as a key factor in neurotransmitter catabolism pathways. However studies to date have reported inconsistent findings regarding the association between the variable number tandem repeat (VNTR) and T941G polymorphisms and schizophrenia. In an attempt to clarify this inconsistency we conducted a meta-analysis based on both alleles and genotypes (up to February 2006). In this study, however, we found no significant evidence of association with the two schizophrenia susceptibility polymorphisms.

    Funded by: NIMH NIH HHS: MH44292

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;2;174-8

  • No evidence for interaction between MAOA and childhood adversity for antisocial behavior.

    Prichard Z, Mackinnon A, Jorm AF and Easteal S

    Predictive Medicine Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia.

    Previous reports have identified an interaction between an MAOA promoter polymorphism and childhood adversity for antisocial behavioral outcomes in males. This study attempted to replicate this finding in an Australian community survey of 1,002 Caucasian men aged 20-24 years. Greater childhood adversity was associated with later antisocial behavior, but no association was observed between MAOA genotype and antisocial behavior, and no interaction was found between childhood adversity and MAOA genotype for antisocial behavior. This study does not support previous reports of an interaction between MAOA genotype and childhood adversity for antisocial behavior in males.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;2;228-32

  • Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality.

    Buckholtz JW, Callicott JH, Kolachana B, Hariri AR, Goldberg TE, Genderson M, Egan MF, Mattay VS, Weinberger DR and Meyer-Lindenberg A

    Neuroimaging Core Facility, National Institute for Mental Health, NIH, DHHS, Bethesda, MD 20892-1365, USA.

    Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

    Molecular psychiatry 2008;13;3;313-24

  • Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women.

    Ducci F, Enoch MA, Hodgkinson C, Xu K, Catena M, Robin RW and Goldman D

    Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852, USA. duccif@mail.nih.gov

    Women who have experienced childhood sexual abuse (CSA) have an increased risk of alcoholism and antisocial personality disorder (ASPD). Among male subjects, a functional polymorphism (MAOA-LPR, monoamine oxidase A linked polymorphic region) in the promoter region of the monoamine oxidase A gene (MAOA) appears to moderate the effect of childhood maltreatment on antisocial behavior. Our aim was to test whether MAOA-LPR influences the impact of CSA on alcoholism and ASPD in a sample of 291 women, 50% of whom have experienced CSA; we also tested whether haplotypes covering the region where both MAOA and monoamine oxidase B (MAOB) genes are located predict risk of alcoholism and ASPD better than the MAOA-LPR locus alone. Participants included 168 alcoholics (39 with ASPD (antisocial alcoholics) and 123 controls (no alcoholics, no ASPD). Antisocial behavior was also modeled as a continuous trait: ASPD symptoms count. The MAOA-LPR low activity allele was associated with alcoholism (P=0.005), particularly antisocial alcoholism (P=0.00009), only among sexually abused subjects. Sexually abused women who were homozygous for the low activity allele had higher rates of alcoholism and ASPD, and more ASPD symptoms, than abused women homozygous for the high activity allele. Heterozygous women displayed an intermediate risk pattern. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women. The MAOA-LPR low activity allele was found on three different haplotypes. The most abundant MAOA haplotype containing the MAOA-LPR low activity allele was found in excess among alcoholics (P=0.008) and antisocial alcoholics (P=0.001). Finally, a MAOB haplotype, which we termed haplotype C, was significantly associated with alcoholism (P=0.006), and to a lesser extent with antisocial alcoholism (P=0.03). In conclusions, MAOA seems to moderate the impact of childhood trauma on adult psychopathology in female subjects in the same way as previously shown among male subjects. The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of CSA. Haplotype-based analysis of the MAOA gene appeared to strengthen the association, as compared to the MAOA-LPR locus alone. A MAOB haplotype was associated with alcoholism independently from ASPD.

    Funded by: Intramural NIH HHS

    Molecular psychiatry 2008;13;3;334-47

  • MAOA and the neurogenetic architecture of human aggression.

    Buckholtz JW and Meyer-Lindenberg A

    Vanderbilt Brain Institute and Department of Psychology, Vanderbilt University, Nashville, TN 37212, USA. joshua.buckholtz@vanderbilt.edu

    Antisocial aggression is a widespread and expensive social problem. Although aggressive behaviors and temperament are highly heritable, clinical and trait associations for the most promising candidate gene for aggression, MAOA, have been largely inconsistent. We suggest that limitations inherent to that approach might be overcome by using multimodal neuroimaging to characterize neural mechanisms of genetic risk. Herein, we detail functional, structural and connectivity findings implicating the low-expressing allele of the MAOA u-VNTR (MAOA-L) in adversely prejudicing information processing within a corticolimbic circuit composed of amygdala, rostral cingulate and medial prefrontal cortex. We propose that the MAOA-L, by causing an ontogenic excess of 5-hydroxytryptamine, labilizes critical neural circuitry for social evaluation and emotion regulation (the 'socioaffective scaffold'), thereby amplifying the effects of adverse early-life experience and creating deleterious sociocognitive biases. Our construct provides a neurobiologically consistent model for gene-environment interactions in impulsive aggression.

    Funded by: Intramural NIH HHS

    Trends in neurosciences 2008;31;3;120-9

  • Genes implicated in serotonergic and dopaminergic functioning predict BMI categories.

    Fuemmeler BF, Agurs-Collins TD, McClernon FJ, Kollins SH, Kail ME, Bergen AW and Ashley-Koch AE

    Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA. bernard.fuemmeler@duke.edu

    Objective: This study addressed the hypothesis that variation in genes associated with dopamine function (SLC6A3, DRD2, DRD4), serotonin function (SLC6A4, and regulation of monoamine levels (MAOA) may be predictive of BMI categories (obese and overweight + obese) in young adulthood and of changes in BMI as adolescents transition into young adulthood. Interactions with gender and race/ethnicity were also examined.

    Participants were a subsample of individuals from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset of 1,584 unrelated individuals with genotype data. Multiple logistic regressions were conducted to evaluate the associations between genotypes and obesity (BMI > 29.9) or overweight + obese combined (BMI > or = 25) with normal weight (BMI = 18.5-24.9) as a referent. Linear regression models were used to examine change in BMI from adolescence to young adulthood.

    Results: Significant associations were found between SLC6A4 5HTTLPR and categories of BMI, and between MAOA promoter variable number tandem repeat (VNTR) among men and categories of BMI. Stratified analyses revealed that the association between these two genes and excess BMI was significant for men overall and for white and Hispanic men specifically. Linear regression models indicated a significant effect of SLC6A4 5HTTLPR on change in BMI from adolescence to young adulthood.

    Discussion: Our findings lend further support to the involvement of genes implicated in dopamine and serotonin regulation on energy balance.

    Funded by: NCI NIH HHS: CA124905-01A1, K07 CA124905, K07 CA124905-01A1; NICHD NIH HHS: P01 HD 31921, P01 HD031921; NIDA NIH HHS: K23 DA 017261, K23 DA017261; NINDS NIH HHS: NS 049067, R01 NS049067

    Obesity (Silver Spring, Md.) 2008;16;2;348-55

  • Genetic evaluation of the serotonergic system in chronic fatigue syndrome.

    Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD and Rajeevan MS

    Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA.

    Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas. Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS.

    Psychoneuroendocrinology 2008;33;2;188-97

  • Lipid levels are associated with a regulatory polymorphism of the monoamine oxidase-A gene promoter (MAOA-uVNTR).

    Brummett BH, Boyle SH, Siegler IC, Zuchner S, Ashley-Koch A and Williams RB

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. brummett@duke.edu

    Background: The monoamine oxidase-A (MAOA) gene plays a vital role in the metabolism of neurotransmitters, e.g, serotonin, norepinephrine, and dopamine. A polymorphism in the promoter region (MAOA-uVNTR) affects transcriptional efficiency. Allelic variation in MAOA-uVNTR has been associated with body mass index (BMI). We extended previous work by examining relations among this polymorphism and serum lipid levels.

    The sample consisted of 74 males enrolled in a study of caregivers for relatives with dementia. Regression models, adjusted for age, race, group status (caregiver/control), and cholesterol lowering medication (yes/no), were used to examine associations between high verses low MAOA-uVNTR activity alleles and total cholesterol, HDL, LDL, VLDL, LDL/HDL ratio, triglycerides, and BMI.

    Results: Higher total cholesterol (p<0.03), LDL/HDL ratio (p<0.01), triglycerides (p<0.02), and VLDL (p<0.02) were associated with low activity MAOA-uVNTR alleles. HDL and LDL were modestly related to MAOA-uVNTR activity, however, they did not reach the conventional significance level (p<0.07 and p<0.10, respectively). BMI (p<0.74) was unrelated to MAOA-uVNTR transcription.

    Conclusions: The present findings suggest that MAOA-uVNTR may influence lipid levels and individuals with less active alleles are at increased health risk.

    Funded by: NHLBI NIH HHS: HL036587-190007, P01 HL036587, P01 HL036587-190007; NIA NIH HHS: AG019605-05, R01 AG019605, R01 AG019605-05

    Medical science monitor : international medical journal of experimental and clinical research 2008;14;2;CR57-61

  • Which genotype of MAO gene that the patients have are likely to be most susceptible to the symptoms of fibromyalgia?

    Gürsoy S, Erdal E, Sezgin M, Barlas IO, Aydeniz A, Alaşehirli B and Sahin G

    School of Medicine, Department of Physical Medicine and Rehabilitation, Gaziantep University, Gaziantep, 27010, Turkey. gursoy@gantep.edu.tr

    The objective of this study was to analyze the genotype distributions and allele frequencies for the MAO-A and MAO-B polymorphism of the MAO gene among the patients with fibromyalgia syndrome (FS). One hundred and seven fibromyalgia patients and 90 unrelated healthy subjects were included into the study. Genomic DNA of 107 FS patients and 90 healthy control subjects were analyzed by polymerase chain reaction. Polymorphism of the MAO gene was: 1-1, 1-3, 3-3, 3-4. The "allele 3" had a 2.7 to 4.8-fold increased transcription activity than the "allele 1". The frequencies of the genotypes of the patients with FS and healthy controls were compared. Although no significant difference was found in genotypes of patients and controls (P = 0.0559), it is likely that "allele 3" could be a more riskful factor for FS than "allele 1" (P = 0.033). Fibromyalgia impact questionnaire was administered to FS group as well as control group. One of our findings is that, the patients whose genotype 3-3 may be mostly affected by the symptoms of FS. In conclusion, it seems plausible to say that MAOA-dependent metabolism of the biological amines may be partly related to high-activated MAO-A, allele 3, in the occurrence of FS among Turkish population.

    Rheumatology international 2008;28;4;307-11

  • Comparison of the structural properties of the active site cavities of human and rat monoamine oxidase A and B in their soluble and membrane-bound forms.

    Upadhyay AK, Wang J and Edmondson DE

    Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.

    Structural properties of the active site cavities in human and rat monoamine oxidases (MAOA and MAOB) have been studied in their detergent-purified and outer mitochondrial membrane (OMM) bound forms using a spin-labeled irreversible inhibitor (ParSL) as an active specific spin probe. ParSL has been found to be 5-10-fold more specific for human MAOB (hMAOB) with a Ki of ca. 20 muM, compared to Ki's in the range of 100-200 muM observed for other human and rat MAOs. Solvent accessibilities of the active-site-bound spin probes have been determined by studying the power saturation properties of the spin probe EPR signals in the presence and absence of a polar paramagnetic reagent NiEDDA and by measuring the extent of spin probe reductions on treatment with excess ascorbic acid. Results presented here show that the spin probe bound to the hMAOA active site is ca. 7-8-fold more accessible than in hMAOB. In contrast, the spin probes covalently attached to the two rat enzyme active sites show comparable accessibilities to each other. On comparison of human versus rat enzymes, the active-site-bound spin probes in the two rat MAOs show ca. 40% less accessibilities compared to the same in hMAOA but ca. 4-5-fold higher accessibilities than in hMAOB active site. The present data thus suggests that the structural properties of the active site cavities in rat MAOs are significantly different compared to those in the two human enzymes, which correlates with the differences reported earlier in the inhibitor specificities between human and rat MAOs.

    Funded by: NIGMS NIH HHS: GM-29433

    Biochemistry 2008;47;2;526-36

  • The MAO-A gene, platelet MAO-B activity and psychosocial environment in adolescent female alcohol-related problem behaviour.

    Nilsson KW, Wargelius HL, Sjöberg RL, Leppert J and Oreland L

    Centre for Clinical Research, Uppsala University, Central Hospital Västerås, S-721 89, Västerås, Sweden. kent.nilsson@ltv.se

    Background: Antisocial behaviour has been associated with polymorphic variants in candidate genes and recently also gene-environmental interaction models have been presented. It has been suggested that antisocial behaviour, associated with alcohol consumption in males, is related to a variation in the monoamine oxidase A gene (MAO-A) promoter. Furthermore, platelet MAO-B activity has in several studies been reported to be low in male alcoholics, while this has not been the case with regard to female alcoholics. Aims of the present study were to: (1) investigate possible interactions between the MAO-A polymorphism, family relations and maltreatment/sexual abuse on adolescent alcohol-related problem behaviour among female adolescents; (2) to investigate if platelet MAO-B enzyme activity interacted with environment to predict female alcohol-related problems.

    Methods: A random sample of 114 female individuals from a total population of 16- and 19-year adolescents from a Swedish county, who volunteered to participate in the study, were interviewed, filled in a questionnaire and a blood sample was drawn.

    Results: In contrast to what has been reported in males, presence of the long (4-repeat) variant of the MAO-A gene in females interacted significantly with an unfavourable environment (poor family relations or maltreatment/abuse/sexual abuse) to increase the risk for high scores of alcohol-related problems. Furthermore, females with low platelet MAO-B activity showed an increased risk of alcohol-related problem behaviour in an unfavourable environment.

    Conclusions: Poor psychosocial environment interacts with the high activity MAO-A genotype and low platelet MAO-B enzyme activity to increase vulnerability for female adolescent alcohol-related problem behaviour.

    Drug and alcohol dependence 2008;93;1-2;51-62

  • An interaction between the norepinephrine transporter and monoamine oxidase A polymorphisms, and novelty-seeking personality traits in Korean females.

    Lee BC, Yang JW, Lee SH, Kim SH, Joe SH, Jung IK, Choi IG and Ham BJ

    Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

    The personality traits associated with the noradrenergic system have not yet been clearly established. In the present study, we investigated the variable number of tandem repeats (VNTR) polymorphism of the norepinephrine transporter (NET) and monoamine oxidase A (MAOA), which are major components of the adrenergic system, to elucidate their relationship with personality. A total of 245 normal female Koreans (age 23.05+/-3.07 years, mean+/-SD) volunteered to take part in this study. They filled out a Korean version of the Temperament and Character Inventory (TCI) and were genotyped for the NET and MAOA-VNTR; the NET T-182C and MAOA-uVNTR polymorphisms were checked. We found significant main effect of NET genotype on novelty seeking (NS) score (F=5.43, p=0.021) and significant interaction between the NET and MAOA-uVNTR polymorphisms on NS score (F=11.06, p=0.001). However, there were no relationship between MAOA-uVNTR polymorphisms and NS score, and no association with other temperamental dimensions and these two polymorphisms. Our findings suggest that this functional polymorphism in the noradrenergic gene is associated with novelty seeking in Korean females.

    Progress in neuro-psychopharmacology & biological psychiatry 2008;32;1;238-42

  • Monoamine oxidase A variant influences antidepressant treatment response in female patients with Major Depression.

    Domschke K, Hohoff C, Mortensen LS, Roehrs T, Deckert J, Arolt V and Baune BT

    Department of Psychiatry, University of Muenster, Albert-Schweitzer-Strasse 11, D-48143 Muenster, Germany. katharina.domschke@ukmuenster.de

    The monoamine oxidase A (MAO-A) has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of Major Depression. In the present study, 340 patients with a Major Depressive Episode (f=194, m=146; DSM-IV) of Caucasian descent were genotyped for the functional MAO-A VNTR. The clinical response to antidepressive pharmacological treatment was assessed by weekly intra-individual changes of HAM-D-21 scores over six weeks. The longer MAO-A alleles (3a, 4, 5) conferred a significant risk of slower and less efficient overall response over the course of 6 weeks of antidepressant treatment in patients with Major Depression, with the effect being restricted to female patients (p=0.028; corrected for multiple testing). The present results suggest that high-activity MAO-A genotypes possibly by consecutively decreased serotonin and/or norepinephrine availability negatively influence antidepressant treatment response during the first six weeks of pharmacological treatment in female patients with Major Depression.

    Progress in neuro-psychopharmacology & biological psychiatry 2008;32;1;224-8

  • A non-additive interaction of a functional MAO-A VNTR and testosterone predicts antisocial behavior.

    Sjöberg RL, Ducci F, Barr CS, Newman TK, Dell'osso L, Virkkunen M and Goldman D

    Uppsala University Centre for Clinical Research, Central Hospital, Västerås, Sweden. sjobergr@mail.nih.gov

    A functional VNTR polymorphism in the promoter of the monoamine oxidase A gene (MAOA-LPR) has previously been shown to be an important predictor of antisocial behavior in men. Testosterone analogues are known to interact with the MAOA promoter in vitro to influence gene transcription as well as in vivo to influence CSF levels of the MAO metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in human males. We examined the possible joint effects of testosterone (measured in CSF) and MAOA-LPR genotype on antisocial personality disorder and scores on the Brown-Goodwin Aggression scale in 95 unrelated male criminal alcoholics and 45 controls. The results confirm that MAOA genotype and CSF testosterone interact to predict antisocial behaviors. The MAOA/testosterone interaction also predicted low levels of CSF MHPG, which tentatively suggests the possibility that the interaction may be mediated by a direct effect on gene transcription. If replicated these findings offer plausible explanations for previous inconsistencies in studies of the relationship between testosterone and male human aggression, as well as for how MAOA genotype may influence aggressive behavior in human males.

    Funded by: Intramural NIH HHS: Z01 AA000306-02

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2008;33;2;425-30

  • Alcohol dependence and polymorphisms of serotonin-related genes: association studies.

    Mokrović G, Matosić A, Hranilović D, Stefulj J, Novokmet M, Oresković D, Balija M, Marusić S and Cicin-Sain L

    Department of Molecular Biology, Ruder Bogkovid Institute, Zagreb, Croatia.

    Variations in 5HT-related genes contribute to the alterations of serotonergic neurotransmission, which is implicated in the etiopathology of alcoholism. In this preliminary study we have tested polymorphisms of genes involved in 5HT transport and turnover for their association with alcohol dependence. A case group of males with type 2 alcoholism (N=59) and a control group of healthy males (N=282), both of Croatian origin, were analyzed for the frequency distribution of polymorphisms in 5HT transporter (5HTT-VNTR2, 5HTT-LPR), monoamine oxidase A (MAOA-uVNTR) and B (MAOB-A/G) and tryptophan hydroxylase 1 (TPH1 A218C) and 2 (TPH2 G-703T) genes. An increase in the frequencies of 10-repeat allele (p = 0.010; OR = 1.73; 95% CI = 1.14-2.60) and 10/10 genotype (p = 0.006; OR = 2.57; 95% CI = 1.32-5.00) of the 5HTT-VNTR2 polymorphism was found in alcoholic patients. No differences between case and control groups were observed for the other tested polymorphisms. Present results support earlier studies implicating the role of 5HTT gene in alcoholism. The increase of sample size (in progress) is expected to enable search of more subtle differences, as well as re-evaluation of these preliminary findings.

    Collegium antropologicum 2008;32 Suppl 1;127-31

  • Brief report: aggression and stereotypic behavior in males with fragile X syndrome--moderating secondary genes in a "single gene" disorder.

    Hessl D, Tassone F, Cordeiro L, Koldewyn K, McCormick C, Green C, Wegelin J, Yuhas J and Hagerman RJ

    Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, 2825 50th Street, Sacramento, CA 95817, USA. david.hessl@ucdmc.ucdavis.edu

    Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine oxidase A (MAOA-VNTR) polymorphisms, in 50 males with FXS ages 8-24 years. Mothers and fathers of participants reported the frequency and severity of aggressive/destructive, self-injurious, and stereotypic behaviors. Polymorphism genotypes were unrelated to age and IQ. Results showed a significant effect of 5-HTTLPR genotype on aggressive/destructive and stereotypic behavior; males with FXS who were homozygous for the high-transcribing long (L/L) genotype had the most aggressive and destructive behavior, and individuals homozygous for the short (S/S) genotype had the least aggression. Those with the L/L genotype also had the highest levels of stereotypic behavior. There was no effect of MAOA-VNTR on behavior; however those with the high-activity, 4-repeat genotype were more likely to be taking SSRI or SNRI medication. This preliminary study prompts consideration of secondary genes that may modify behavioral phenotype expression in neurodevelopmental disorders, even those with a single gene etiology such as FXS.

    Funded by: NICHD NIH HHS: HD36071; NIMH NIH HHS: MH77554

    Journal of autism and developmental disorders 2008;38;1;184-9

  • Hyperserotonemia in autism: the potential role of 5HT-related gene variants.

    Hranilović D, Novak R, Babić M, Novokmet M, Bujas-Petković Z and Jernej B

    Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, Croatia. dubravka@zg.biol.pmf.hr

    Increased platelet serotonin level (PSL) has been consistently found in a portion of autistic patients. Suggested mechanisms for hyperserotonemia in autism have been increased synthesis of serotonin (5HT) by tryptophan hydroxylase (TPH), increased uptake into platelets through 5HT transporter (5HTt), diminished release from platelets through 5HT2A receptor (5HT2Ar) and decreased metabolism by monoamine oxydase (MAOA). The allelic influence of genes, encoding the mentioned 5HT elements, on PSL was investigated in 63 autistic subjects. Our study shows that 5HTt-LPR and -1438AG 5HT(2Ar) genotypes did not significantly affect PSL. However, significantly higher PSLs were observed in subjects with "cc" genotype of a218c TPH and subjects with "4" genotype of uVNTR MAOA. In addition, when TPH-cc and MAOA-4 were combined as "high 5HT" genotypes, a correlative increase in PSL was observed with the increase in the number of "high 5HT" genotypes. These results suggest a possible synergistic effect of genes regulating 5HT synthesis/degradation in dysregulation of the peripheral 5HT homeostasis of autistic patients.

    Collegium antropologicum 2008;32 Suppl 1;75-80

  • Interactions between genotype and retrospective ADHD symptoms predict lifetime smoking risk in a sample of young adults.

    McClernon FJ, Fuemmeler BF, Kollins SH, Kail ME and Ashley-Koch AE

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Cneter, Durham, NC 27708, USA. mccle011@mc.duke.edu

    Attention-deficit/hyperactivity disorder (ADHD) symptoms are associated with an increased risk of smoking, and genetic studies have identified similar candidate genes associated with both ADHD and smoking phenotypes. This paper addresses the question of whether ADHD symptoms interact with candidate gene variation to predict smoking risk. Participants were a subsample of individuals from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset from Add Health of 1,900 unrelated individuals with genotype data. Multiple logistic regression was used to examine relationships between self-reported ADHD symptoms, genotype, and lifetime history of regular smoking. Polymorphisms in the DRD2 gene and, among females, the MAOA gene interacted with retrospective reports of ADHD symptoms in contributing to risk for smoking. Trends were observed for interactions between the DRD4 gene and, among males, the MAOA gene and ADHD symptoms to predict smoking risk. No main effect for any of these polymorphisms was observed. We observed neither main effects nor interactions with CYP2A6, DAT, and SLC6A4 genes. These findings suggest that genotypes associated with catecholamine neurotransmission interact with ADHD symptoms to contribute to smoking risk.

    Funded by: NICHD NIH HHS: HD31921; NIDA NIH HHS: DA017261; NINDS NIH HHS: NS049067

    Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 2008;10;1;117-27

  • The MAOA promoter polymorphism, disruptive behavior disorders, and early onset substance use disorder: gene-environment interaction.

    Vanyukov MM, Maher BS, Devlin B, Kirillova GP, Kirisci L, Yu LM and Ferrell RE

    Department of Pharmaceutical Sciences, Center for Education and Drug Abuse Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. mmv@pitt.edu

    Objectives: Conduct, oppositional defiant, and attention deficit hyperactivity disorders, reflecting early antisociality and behavior dysregulation, are predictive of substance use disorders. Liabilities to these disorders share genetic and environmental variance. Parenting characteristics have been shown to influence development of antisociality, moderated by variation at the MAOA gene, which has also been associated with the risk for substance use disorders. To extend these findings, we tested the relationships between the MAOA promoter polymorphism (variable number tandem repeat), indices of child's perception of paternal and maternal parenting, and disruptive behavior disorders and substance use disorders.

    Methods: A sample of 148 European-American males was assessed prospectively at ages from 10-12 to 18-19 years and genotyped for the monoamine oxidase A variable number tandem repeat. The Diagnostic and statistical manual of mental disorder-III-R diagnoses were obtained using standard methodology. Parenting was assessed using a scale summarizing the child's evaluation of the parenting style (parent's behavior toward him, parental emotional distance and involvement). Correlation, logistic regression, and Cox proportional hazard regression analysis was used to determine the relationships between the variables.

    Results: The strength of association between parenting index and conduct and attention deficit hyperactivity disorders depended on the MAOA genotype. Unlike earlier findings, the parenting-risk relationships were observed in the 'high-' rather than 'low-activity' genotypes. The strength and direction of relationships depended on the parental sex. The MAOA polymorphism's association with the risk for substance use disorders was detected when parenting was controlled for.

    Conclusions: The results are consistent with the contribution of the MAOA gene, parenting style and their interactions to variation in the risk for early onset behavior disorders and liability to substance use disorders.

    Funded by: NIDA NIH HHS: K02DA017822, K02DA018701, P50DA005605, R01DA011922, R01DA019157

    Psychiatric genetics 2007;17;6;323-32

  • Monoamine oxidase-A modulates apoptotic cell death induced by staurosporine in human neuroblastoma cells.

    Fitzgerald JC, Ufer C, De Girolamo LA, Kuhn H and Billett EE

    School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton, Nottingham, UK.

    Monoamine oxidases (MAOs) are mitochondrial enzymes which control the levels of neurotransmitters in the brain and dietary amines in peripheral tissues via oxidative deamination. MAO has also been implicated in cell signalling. In this study, we describe the MAO-A isoform as functional in apoptosis induced by staurosporine (STS) in human dopaminergic neuroblastoma cells (SH-SY5Y). Increased levels of MAO-A activity were induced by STS, accompanied by increased MAO-A protein and activation of the initiator of the intrinsic pathway, caspase 9, and the executioner caspase 3. MAO-A mRNA levels were unaffected by STS, suggesting that changes in MAO-A protein are due to post-transcriptional events. Two unrelated MAO-A inhibitors reduced caspase activation. STS treatment resulted in sustained activation of the mitogen-activated protein kinase pathway enzymes extracellular regulated kinase, c-jun terminal kinase and p38, and depletion of the anti-apoptotic protein Bcl-2. These changes were significantly reversed by MAO inhibition. Production of reactive oxygen species was increased following STS exposure, which was blocked by both MAO inhibition and the antioxidant N-acetylcysteine. Therefore our data provide evidence that MAO-A, through its production of reactive oxygen species as a by-product of its catalytic activity on the mitochondrial surface, is recruited by the cell to enhance apoptotic signalling.

    Journal of neurochemistry 2007;103;6;2189-99

  • Association analysis of 15 polymorphisms within 10 candidate genes for antisocial behavioural traits.

    Prichard ZM, Jorm AF, Mackinnon A and Easteal S

    Predictive Medicine Group, John Curtin School of Medical Research, University of Melbourne, Australia.

    This study sought to test 15 simple sequence repeat polymorphisms within 10 candidate genes for association with antisocial behavioural traits. Genes included were those known to regulate dopamine synthesis and transmission in the brain (DBH, DRD2, MAOA, TFAP2B, NR4A2, LMX1B) and those involved in the differentiation of social and sexual behaviour in men and women (AR, ESR1, OXTR, AVPR1A). Participants were Caucasians (men=1007, women=1089) aged 20-24 years who were assessed for indicators of antisocial traits such as pseudo-maturity, substance misuse and unstable lifestyle. Significant associations for antisocial traits were found with AR and ESR1 polymorphisms in men, and with polymorphisms within NR4A2 and TFAP2B in women. The association with TFAP2B remained significant after correction for multiple testing. This pattern of associations suggests that genetic variation within transcription factors may in part explain the variation observed in the population for antisocial behavioural phenotypes.

    Psychiatric genetics 2007;17;5;299-303

  • Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior.

    Tochigi M, Suzuki K, Kato C, Otowa T, Hibino H, Umekage T, Kato N and Sasaki T

    Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

    Objective: The genes of catalytic enzymes of dopamine, including monoamine oxidase (MAOA and MAOB) and catechol-O-methyltransferase (COMT), have been major candidates for genes that affect smoking behavior. In this study, we investigated the relationship between smoking behavior and four polymorphisms of these genes, the MAOA variable number tandem repeat polymorphism, the MAOA 1460 T/C polymorphism, the MAOB intron 13 G/A polymorphism, and the COMT Val158Met polymorphism. The association between the MAOB polymorphism and personality traits was also explored.

    The polymorphisms were genotyped in 451 healthy Japanese volunteers. Data on smoking habits were obtained from structured interviews. In addition to testing the association between each polymorphism and smoking status, epistatic and additive effects between two polymorphisms were also investigated.

    Results: A significant association was observed between the COMT Val158Met polymorphism and smoking status. Male participants with the Val/Val genotype had a significantly higher risk of heavy smoking compared with those with other genotypes, although no significant association was observed in female participants. No evidence was obtained for an association between the MAO genes and smoking behavior, including epistatic or additive effects. No significant association was observed between the MAOB polymorphism and personality traits.

    Conclusion: This study may suggest a role of the COMT Val158Met polymorphism in smoking behavior in Japanese individuals.

    Pharmacogenetics and genomics 2007;17;10;867-72

  • Gene-environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study.

    Dick FD, De Palma G, Ahmadi A, Osborne A, Scott NW, Prescott GJ, Bennett J, Semple S, Dick S, Mozzoni P, Haites N, Wettinger SB, Mutti A, Otelea M, Seaton A, Soderkvist P, Felice A and Geoparkinson Study Group

    Department of Environmental and Occupational Medicine, University of Aberdeen, UK. f.dick@abdn.ac.uk

    Objectives: To investigate associations of Parkinson's disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk.

    Methods: A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX, DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders.

    Results: There was a modest but significant association between MAO-A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only).

    Conclusions: Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.

    Occupational and environmental medicine 2007;64;10;673-80

  • Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology.

    Cao X, Wei Z, Gabriel GG, Li X and Mousseau DD

    The Cell Signalling Laboratory, Neuropsychiatry Research Unit, University of Saskatchewan, 103 Wiggins Road, Saskatoon, SK S7N 5E4, Canada. caoxia25@hotmail.com

    Background: Calcium (Ca2+) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD).

    Results: Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca2+-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation) associated with either A23187 or the AD-related beta-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures.

    Conclusion: These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.

    BMC neuroscience 2007;8;73

  • A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients.

    Wu YH, Fischer DF and Swaab DF

    Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.

    Background: Monoamine oxidase A (MAOA) is involved in the pathogenesis of mood disorders and Alzheimer's disease (AD). MAOA activity and gene expression have been found to be up-regulated in different brain areas of AD patients, including the pineal gland. Increased pineal MAOA activity might contribute to the reduced pineal melatonin production in AD. A promoter polymorphism of a variable number tandem repeats (VNTR) in the MAOA gene shows to affect MAOA transcriptional activity in vitro.

    Methods: Here we examined in 63 aged controls and 44 AD patients the effects of the MAOA-VNTR on MAOA gene expression and activity in the pineal gland as endophenotypes, and on melatonin production.

    Results: AD patients carrying long MAOA-VNTR genotype (consisting of 3.5- or 4-repeat alleles) showed higher MAOA gene expression and activity than the short-genotyped (i.e., 3-repeat allele) AD patients. Moreover, the AD-related up-regulation of MAOA showed up only among long-genotype bearing subjects. There was no significant effect of the MAOA-VNTR on MAOA activity or gene expression in controls, or on melatonin production in both controls and AD patients.

    Conclusion: Our data suggest that the MAOA-VNTR affects the activity and gene expression of MAOA in the brain of AD patients, and is involved in the changes of monoamine metabolism.

    Brain research 2007;1167;13-9

  • Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects.

    Fowler JS, Alia-Klein N, Kriplani A, Logan J, Williams B, Zhu W, Craig IW, Telang F, Goldstein R, Volkow ND, Vaska P and Wang GJ

    Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. fowler@bnl.gov

    Background: A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects.

    Methods: Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism.

    Results: There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes.

    Conclusions: The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.

    Funded by: NCRR NIH HHS: M01 RR010710, M01 RR010710-11, M01 RR10710; NIBIB NIH HHS: EB002630, R01 EB002630; NIDA NIH HHS: K05 DA020001, K05 DA020001-03, K05 DA020001-04, K05 DA02001

    Biological psychiatry 2007;62;4;355-8

  • Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes.

    Bour S, Daviaud D, Gres S, Lefort C, Prévot D, Zorzano A, Wabitsch M, Saulnier-Blache JS, Valet P and Carpéné C

    U858 INSERM, I2MR, IFR 31, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France.

    A strong induction of semicarbazide-sensitive amine oxidase (SSAO) has previously been reported during murine preadipocyte lineage differentiation but it remains unknown whether this emergence also occurs during adipogenesis in man. Our aim was to compare SSAO and monoamine oxidase (MAO) expression during in vitro differentiation of human preadipocytes and in adipose and stroma-vascular fractions of human fat depots. A human preadipocyte cell strain from a patient with Simpson-Golabi-Behmel syndrome was first used to follow amine oxidase expression during in vitro differentiation. Then, human preadipocytes isolated from subcutaneous adipose tissues were cultured under conditions promoting ex vivo adipose differentiation and tested for MAO and SSAO expression. Lastly, human adipose tissue was separated into mature adipocyte and stroma-vascular fractions for analyses of MAO and SSAO at mRNA, protein and activity levels. Both SSAO and MAO were increased from undifferentiated preadipocytes to lipid-laden cells in all the models: 3T3-F442A and 3T3-L1 murine lineages, human SGBS cell strain or human preadipocytes in primary culture. In human subcutaneous adipose tissue, the adipocyte-enriched fraction exhibited seven-fold higher amine oxidase activity and contained three- to seven-fold higher levels of mRNAs encoded by MAO-A, MAO-B, AOC3 and AOC2 genes than the stroma-vascular fraction. MAO-A and AOC3 genes accounted for the majority of their respective MAO and SSAO activities in human adipose tissue. Most of the SSAO and MAO found in adipose tissue originated from mature adipocytes. Although the mechanism and role of adipogenesis-related increase in amine oxidase expression remain to be established, the resulting elevated levels of amine oxidase activities found in human adipocytes may be of potential interest for therapeutic intervention in obesity.

    Biochimie 2007;89;8;916-25

  • [Association study of the polymorphisms of monoamine oxidase A genes with schizophrenia].

    Shi YZ, Wang CH, Lv LX, Wang YH, Zhang HX and Lou BY

    Department of Psychiatry, the Second Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, 453002 P. R. China.

    Objective: To investigate the relationship between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia in a Chinese Han population.

    Methods: Two hundred and twelve schizophrenic patients and 168 healthy controls were recruited according to CCMD-3. The polymorphisms of MAOA gene were determined with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The case-control association analysis was adopted to analyze the frequencies of genotype and allele in schizophrenic patients and controls.

    Results: (1) The genotypes of MAOA gene were consistent with Hardy-Weinberg equilibrium in patient group and control group (chi2 = 0.618, df= 2, P> 0.05; chi2 = 3.173, df= 2, P> 0.05). (2) The distributions of genotypes or alleles of MAOA genes had no significant difference between patient group and control group (P> 0.05). (3)Divided by sex, the frequency of CT genotype in male patients was higher than that in male controls (chi2 = 7.654, P= 0.022). (4) There were no significant differences of genotypic and allelic distribution in MAOA genes between schizophrenic patients with positive family history and schizophrenic patients with negative family history and among different clinical subtypes in schizophrenic patients (P> 0.05).

    Conclusion: No association between MAOA gene and schizophrenia is found in Chinese Han population, but CT genotype is likely to be a susceptible factor of male schizophrenia.

    Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2007;24;4;457-9

  • The influence of four serotonin-related genes on decision-making in suicide attempters.

    Jollant F, Buresi C, Guillaume S, Jaussent I, Bellivier F, Leboyer M, Castelnau D, Malafosse A and Courtet P

    Université Montpellier 1, Montpellier, France. f-jollant@chu-montpellier.fr

    Genetic factors have been associated with the vulnerability to suicidal behavior. We previously reported decision-making impairment in suicide attempters and hypothesized that these cognitive alterations may represent an endophenotype of suicidal behavior. In this study, we aimed to investigate the influence of four serotonin-related genes relevant to suicidal behavior on decision-making, in a large population of suicide attempters. The Iowa Gambling Task was used to assess decision-making in 168 patients with a personal history of attempted suicide. Patients were genotyped for four serotonergic polymorphisms: 5HTTLPR, TPH1 A218C, MAOA u-VNTR, and TPH2 rs1118997. Patients carrying the 5HTTLPR-ll and -sl, TPH1-CC and -AC, MAOA-HH (in women) and TPH2-AA genotypes significantly improved their performance during the task, suggesting a genetic modulation of the learning process required for advantageous decision-making. In contrast, genotypes previously associated with a higher risk of suicidal behavior, a greater sensitivity to the environment and a higher propensity to negative feelings are those conferring poorer learning abilities. We hypothesize that the influence of genetic factors on the vulnerability to suicidal behavior may partly be achieved through their modulation of decision-making and particularly its learning component.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;5;615-24

  • [Genetic basis of time perception in athletes].

    Portnova GV, Sysoeva OV, Maliuchenko NV, Timofeeva MA, Kulikova MA, Tonevitskiĭ AG, Kirpichnikov MP and Ivanitskiĭ AM

    The association between the subjective time perception and polymorphism of some genes, regulating activity of serotonin and dopamine, was studied in 89 synchronized swimmers. COMT gene, responsible for dopamine destruction, influences on reproduction of short time intervals (1-2 s). 5-HT2A and MAOA genes, regulating activity of serotonin, influence on subjective time flow. 5-HTT and COMT genes, regulating activity of serotonin and dopamine respectively, are related with accuracy of orientation in time. Association of time perception with different genes and mediators suggests different perception mechanisms, in different time ranges, in concordance with the previous physiological studies. The current study reveals that these physiological mechanisms have different molecular-neurochemical basis that helps to overcome the gap between the investigation on systemic and molecular levels.

    Zhurnal vysshei nervnoi deiatelnosti imeni I P Pavlova 2007;57;4;450-60

  • [Genetic polymorphism of a MAO in mental disorders].

    Tylec A, Stryjecka-Zimmer M and Kucharska-Pietura K

    Katedra i Klinika Psychiatrii AM w Lublinie.

    Amin oxydase (monoaminoxydase, MAO) is an enzyme which catalyses chemical reactions of biogenic amines. It plays a crucial role in pathogenesis of mental disorders associated with the dysfunction of the central monoaminergic systems (schizophrenia, affective disorders, some forms of alcohol dependence, and personality disorders). MAO has got two isoforms such as MAO-A and MAO-B. The genes coding of MAO are localised at the short arm of chromosome Xp11. In each sequence of genes there is a probability of functional polymorphism occurrence which leads to a variable expression or a change of MAO activity and it exerts an impact on the onset of some mental disorders, such as: schizophrenia, affective disorders, some forms of alcohol dependence, and personality and behavioural disorders. Dynamic development of psychiatric genetics may have crucial impact on considerable progress in understanding molecular background of mental disorders.

    Psychiatria polska 2007;41;4;485-93

  • [Genetic polymorphism of COMT in mental disorders].

    Tylec A, Stryjecka-Zimmer M and Kucharska-Pietura K

    Katedra i Klinika Psychiatrii AM w Lublinie.

    Many neurobiochemical studies show abnormalities within dopaminergic neuropathways, particularly altered dopamine transmission in etiopathogenesis of mental disorders. Evaluation of genes associated with the dopaminergic system include five well known subtypes of dopaminergic receptors, dopamine transporter and enzymes associated with the synthesis and degradation of dopamine, such as tyrosine hydroxylase, dopa decarboxylase, monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). None of these genes is 'a' pathognomonic factor of schizophrenia onset. In each sequence of the following genes 'a' functional polymorphism can occur. The polymorphisms of genes MAO-A and COMT have been described in relation to various expression or altered activity of these enzymes, their influence on cognitive functions, affective and anxiety disorders, learning disabilities, aggressive behaviour, eating disorders or gender differences.

    Psychiatria polska 2007;41;4;473-83

  • Gene-lifecourse interaction for alcohol consumption in adolescence and young adulthood: five monoamine genes.

    Guo G, Wilhelmsen K and Hamilton N

    Carolina Population Center, University of North Carolina at Chapel Hill, North Carolina 27599-3210, USA. guang_guo@unc.edu

    Association analysis has suggested that common sequence variants of genes that affect monoamine function can affect substance use and abuse. Demonstration of these associations has been inconsistent because of limited sample sizes and phenotype definition. Drawing on the life course perspective, we predicted a stronger association between the polymorphisms in 5HTT, DAT1, DRD4, DRD2, and MAOA and alcohol consumption in young adulthood than adolescence. This analysis tested for the gene-lifecourse interaction for the frequency of alcohol consumption in a nationally representative non-alcohol-dependent sample of 2,466 individuals that were visited during adolescence and young adulthood for four times between 1994 and 2002. All five genes are significantly associated with the frequency of alcohol consumption, with the genotype effects ranging 7%-20% of the mean score of alcohol consumption and their P values being 0.014, 0.0003, 0.003, 0.007, 0.005, and 0.003, respectively. The association is only observed in the life stage of young adulthood and not in adolescence. This analysis has demonstrated the potential usefulness of the life course perspective in genetic studies of human behaviors such as alcohol consumption.

    Funded by: NICHD NIH HHS: P01-HD31921, R03-HD042490-02

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;4;417-23

  • Monoamine oxidase A gene polymorphism predicts adolescent outcome of attention-deficit/hyperactivity disorder.

    Li J, Kang C, Zhang H, Wang Y, Zhou R, Wang B, Guan L, Yang L and Faraone SV

    Institute of Mental Health, Peking University (Peking University sixth hospital), China.

    ADHD is generally deemed to be a highly heritable disorder with mean heritability of 0.75. The enzyme monoamine oxidase (MAO), which has both A and B types, has long been considered a candidate pathological substrate for ADHD, and more recently, the genes for both MAO enzymes have been examined as mediators of the illness. Previous studies indicated that 30-50% of children with ADHD will experience symptoms that persist into adolescence and will have more significant impairment in social and neuropsychological functioning compared to those whose symptoms have remitted. Genes may also influence these characteristics of the disorder, and in this context MAO genes may also be candidates for moderating the presentation of ADHD. The current study examined the association between adolescent outcome of ADHD and MAO gene polymorphisms, including the 941T > G polymorphism in exon 8 (rs1799835) and 1460C > T polymorphism in exon 14 (rs1137070) of the MAOA gene, and the A > G polymorphism in intron13 (rs1799836), C > T polymorphism in the 3'UTR (rs1040399), and 2327T > C polymorphism in exon15 of the MAOB gene. Significant associations were observed between the MAOA gene polymorphisms and ADHD remission. Due to the small sample size and the possibility of phenotypic and etiologic heterogeneity of ADHD outcomes across ethnic or geographic groups, these results must be replicated before they can be generalized to other populations.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;4;430-3

  • Association study between clinical response to rizatriptan and some candidate genes.

    Asuni C, Cherchi A, Congiu D, Piccardi MP, Del Zompo M and Stochino ME

    Section of Clinical Pharmacology, Department of Neurosciences B.B. Brodie, University of Galiari, P.O. San Giovanni di Dio, Via Ospedale 46, I-09124 Cagliari, Italy. carloasuni@tiscali.it

    The aim of this study was to test genetic differences in the clinical response to rizatriptan in patients affected by migraine without aura. These genetic differences could be explained by various genes, the HTR1B, encoding the 5-HT(1) receptor subtype, MAOA gene that encodes the monoamino-oxidase, the main metabolic enzyme of this triptan, SLC6A4 (gene encoding the serotonin transporter) and DRD(2) (gene encoding the D(2) receptor), both involved in the pathogenesis of migraine. Fifty unrelated patients affected by migraine without aura (IHS) were included. Patients were divided into two groups (responders and non-responders) according to clinical response. Thirty-one out of fifty patients responded to rizatriptan. A significant difference among the two groups was observed in both allele (p=0.02) and genotype distribution (p=0.03) of DRD2/NcoI. The significant association with the DRD2/NcoI polymorphism in responders suggested that the DRD2/NcoI C allele may be considered a susceptibility factor heralding a good response to rizatriptan.

    The journal of headache and pain 2007;8;3;185-9

  • Associations of a regulatory polymorphism of monoamine oxidase-A gene promoter (MAOA-uVNTR) with symptoms of depression and sleep quality.

    Brummett BH, Krystal AD, Siegler IC, Kuhn C, Surwit RS, Züchner S, Ashley-Koch A, Barefoot JC and Williams RB

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. brummett@duke.edu

    Objective: To examine the relationships among the variable number of tandem repeats in the monoamine oxidase-A linked polymorphic region allelic variation (MAOA-uVNTR) and the symptoms of depression and sleep quality. The monoamine oxidase-A (MAOA) gene, which plays a vital role in degradation of neurotransmitters such as serotonin, norepinephrine, and dopamine, contains a polymorphism in its promoter region (MAOA-uVNTR) that affects transcriptional efficiency. MAOA-uVNTR genotype has been associated with both psychological and physical measures.

    Methods: The sample consisted of 74 males enrolled in a case/control study of caregivers for relatives with dementia. Age- and race-adjusted linear regression models were used to examine the association between low versus high MAOA-uVNTR activity alleles, symptoms of depression (Center for Epidemiological Studies of Depression), and sleep quality ratings (Pittsburgh Sleep Quality Index).

    Results: MAOA-uVNTR alleles associated with less transcriptional activity were related to increased symptoms of depression (p < .04; Cohen's d = 0.52) and poorer sleep quality (p < .04; Cohen's d = 0.31).

    Conclusions: Individuals with less active MAOA-uVNTR alleles may be at increased risk for depressive symptoms and poor sleep.

    Funded by: NCRR NIH HHS: M01RR30; NHLBI NIH HHS: 3P01 HL036587, P01 HL036587, P01 HL036587-190007; NIA NIH HHS: R01 AG019605, R01 AG019605-05, R01AG19605; NIMH NIH HHS: R01 MH057663, R01MH57663

    Psychosomatic medicine 2007;69;5;396-401

  • Monoamine oxidase a gene is associated with borderline personality disorder.

    Ni X, Sicard T, Bulgin N, Bismil R, Chan K, McMain S and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. xingqun_ni@camh.net

    Objective: Monoamine oxidase A is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines: serotonin and norepinephrine. As for its role in aggression, impulsivity, suicide and mood liability, monoamine oxidase A can be considered a functional candidate in borderline personality disorder.

    Methods: To test for this hypothesis we genotyped two polymorphic markers in monoamine oxidase A gene, a promoter VNTR and an rs6323 (T941G) in exon 8, in 111 Caucasian borderline personality disorder patients and 289 Caucasian healthy controls. Association analyses using individual marker and haplotype data were performed by a program of COCAPHASE in UNPHASED (MRC Human Genome Mapping Project Resource Centre, Cambridge, UK).

    Results: We found that the borderline personality disorder patients had a high frequency of the high activity VNTR alleles (chi=4.696, P=0.03) and a low frequency of the low activity haplotype (chi=5.089, P=0.02).

    Conclusion: These results show that the monoamine oxidase A gene may play an important role in the etiological development of the borderline personality disorder.

    Psychiatric genetics 2007;17;3;153-7

  • Early trauma and increased risk for physical aggression during adulthood: the moderating role of MAOA genotype.

    Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, Gross C and Troisi A

    European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo, Italy.

    Previous research has reported that a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter can moderate the association between early life adversity and increased risk for violence and antisocial behavior. In this study of a combined population of psychiatric outpatients and healthy volunteers (N = 235), we tested the hypothesis that MAOA genotype moderates the association between early traumatic life events (ETLE) experienced during the first 15 years of life and the display of physical aggression during adulthood, as assessed by the Aggression Questionnaire. An ANOVA model including gender, exposure to early trauma, and MAOA genotype as between-subjects factors showed significant MAOAxETLE (F(1,227) = 8.20, P = 0.005) and genderxMAOAxETLE (F(1,227) = 7.04, P = 0.009) interaction effects. Physical aggression scores were higher in men who had experienced early traumatic life events and who carried the low MAOA activity allele (MAOA-L). We repeated the analysis in the subgroup of healthy volunteers (N = 145) to exclude that the observed GxE interactions were due to the inclusion of psychiatric patients in our sample and were not generalizable to the population at large. The results for the subgroup of healthy volunteers were identical to those for the entire sample. The cumulative variance in the physical aggression score explained by the ANOVA effects involving the MAOA polymorphism was 6.6% in the entire sample and 12.1% in the sub-sample of healthy volunteers. Our results support the hypothesis that, when combined with exposure to early traumatic life events, low MAOA activity is a significant risk factor for aggressive behavior during adulthood and suggest that the use of dimensional measures focusing on behavioral aspects of aggression may increase the likelihood of detecting significant gene-by-environment interactions in studies of MAOA-related aggression.

    PloS one 2007;2;5;e486

  • Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

    Jabbi M, Korf J, Kema IP, Hartman C, van der Pompe G, Minderaa RB, Ormel J and den Boer JA

    Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands. m.jabbi@med.umcg.nl

    Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

    Molecular psychiatry 2007;12;5;483-90

  • Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence.

    Huang SY, Lin WW, Wan FJ, Chang AJ, Ko HC, Wang TJ, Wu PL and Lu RB

    Department of Psychiatry, Tri-Service General Hospital, Taiwan, ROC.

    Objective: Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene.

    Methods: A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria.

    Conclusion: The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype.

    Journal of psychiatry & neuroscience : JPN 2007;32;3;185-92

  • The MAOA T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major depression.

    Tadić A, Müller MJ, Rujescu D, Kohnen R, Stassen HH, Dahmen N and Szegedi A

    Department of Psychiatry, University of Mainz, Mainz, Germany. tadic@uni-mainz.de

    This study investigated the possible association of the MAOA T941G gene variant with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized double-blind controlled clinical trial. Female mirtazapine-treated patients homozygous for the T-allele had a significantly faster and better treatment response than TG/GG-patients. In males, we failed to show an association between MAOA T941G gene variant and mirtazapine response. In the paroxetine-treated group, there were no significant differences in treatment response between MAOA T941G genotype groups. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the MAOA gene, at least in female patients. An independent replication of our finding is needed. If replicated, genotyping of this locus could become a promising tool to predict response to mirtazapine treatment in females suffering from major depression.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;3;325-31

  • Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells.

    Tu LC, Yan X, Hood L and Lin B

    Institute for Systems Biology, Seattle, Washington 98103, USA.

    NDRG1 is known to play important roles in both androgen-induced cell differentiation and inhibition of prostate cancer metastasis. However, the proteins associated with NDRG1 function are not fully enumerated. Using coimmunoprecipitation and mass spectrometry analysis, we identified 58 proteins that interact with NDRG1 in prostate cancer cells. These proteins include nuclear proteins, adhesion molecules, endoplasmic reticulum (ER) chaperons, proteasome subunits, and signaling proteins. Integration of our data with protein-protein interaction data from the Human Proteome Reference Database allowed us to build a comprehensive interactome map of NDRG1. This interactome map consists of several modules such as a nuclear module and a cell membrane module; these modules explain the reported versatile functions of NDRG1. We also determined that serine 330 and threonine 366 of NDRG1 were phosphorylated and demonstrated that the phosphorylation of NDRG1 was prominently mediated by protein kinase A (PKA). Further, we showed that NDRG1 directly binds to beta-catenin and E-cadherin. However, the phosphorylation of NDRG1 did not interrupt the binding of NDRG1 to E-cadherin and beta-catenin. Finally, we showed that the inhibition of NDRG1 expression by RNA interference decreased the ER inducible chaperon GRP94 expression, directly proving that NDRG1 is involved in the ER stress response. Intriguingly, we observed that many members of the NDRG1 interactome are androgen-regulated and that the NDRG1 interactome links to the androgen response network through common interactions with beta-catenin and heat shock protein 90. Therefore we overlaid the transcriptomic expression changes in the NDRG1 interactome in response to androgen treatment and built a dual dynamic picture of the NDRG1 interactome in response to androgen. This interactome map provides the first road map for understanding the functions of NDRG1 in cells and its roles in human diseases, such as prostate cancer, which can progress from androgen-dependent curable stages to androgen-independent incurable stages.

    Funded by: NCI NIH HHS: 1U54CA119347, 5P01CA085859, 5P50CA097186; NIDA NIH HHS: 1U54DA021519; NIGMS NIH HHS: 1P50GM076547, P50 GM076547

    Molecular & cellular proteomics : MCP 2007;6;4;575-88

  • Gene-gene interaction analysis of personality traits in a Japanese population using an electrochemical DNA array chip analysis.

    Urata T, Takahashi N, Hakamata Y, Iijima Y, Kuwahara N, Ozaki N, Ono Y, Amano M and Inada T

    TUM Gene Inc., Chiba, Japan.

    It has been suggested that genes involved in the central dopaminergic pathway may contribute to personality traits. However, the results of association studies for these genes have not been consistent. The present study investigated the relationship between the specific polymorphisms of MAO-A, COMT, DRD2, DRD3 and personality traits in Japanese women using a novel genotyping method involving electrochemical DNA array (ECA) chip analysis. Single marker association analysis for each mutation revealed no significant association between scores for Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) items. Gene-gene interaction analysis showed that a MAO-A 30-bp repeatxCOMT (Val158Met)xDRD3 (Ser9Gly) had a marginally significant association with Agreeableness (P=0.0547). The present results suggest that a combination of polymorphisms of MAO-A, COMT, and DRD3 might affect personality traits in Japanese women.

    Neuroscience letters 2007;414;3;209-12

  • Adolescent girls and criminal activity: role of MAOA-LPR genotype and psychosocial factors.

    Sjöberg RL, Nilsson KW, Wargelius HL, Leppert J, Lindström L and Oreland L

    Centre for Clinical Research, Uppsala University, Central Hospital Västerås, Västerås, Sweden. rickard.sjoberg@ltv.se

    Recent findings among boys show that interactions between a polymorphism in the monoamine oxidase A gene promoter region (MAOA-LPR) and psychosocial factors predict criminal activity. The objective of this study was to investigate whether this finding could be extended to adolescent girls. One hundred nineteen female adolescents were recruited among respondents to a cross-sectional study of the total population of 16- and 19-year old girls. These girls constituted a randomly selected sub-sample from groups representing different degrees of risk behavior. The subjects filled in a questionnaire and were interviewed and genotyped with regard to MAOA-LPR. The results indicate that the long, (4-repeat) allele confer an increased risk for criminal behavior in the presence of psychosocial risk. Among girls without social risk, MAOA-LPR genotype was of no importance for criminal behavior. The present results suggest that previous observations on adolescent males, which demonstrate that the short MAOA-LPR genotype and psychosocial adversity interact to predict criminal activity, may not be applicable to females.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;2;159-64

  • The importance of stress and genetic variation in human aggression.

    Craig IW

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London PO82, De Crespigny Park, London SE5 8AF, UK. i.craig@iop.kcl.ac.uk

    Both genetic and environmental factors have key roles in determining aggressive tendencies. In particular, reaction to stress appears to be an important factor in precipitating aggressive episodes and individuals may vary in their ability to cope with stressful environments depending on their genetic make up. Evidence from humans and primates indicates that adverse rearing conditions may interact with variants in stress and neurotransmitter pathway genes leading to antisocial and/or violent behaviour. Common alleles of some serotonin pathway genes, including those involved in its degradation (monoamine oxidase A, MAOA), or its re-uptake into pre-synaptic neurones (serotonin transporter, SERT) have been shown to confer functional variation. Examination of the interaction between the alleles of such polymorphisms (in particular those affecting MAOA) and environmental stressors suggest that they may provide protection against, or increase sensitivity to, abusive upbringing; an observation that may explain part of the variability in developmental outcomes associated with maltreatment.

    BioEssays : news and reviews in molecular, cellular and developmental biology 2007;29;3;227-36

  • The monoamine oxidase A (MAO-A) gene, family function and maltreatment as predictors of destructive behaviour during male adolescent alcohol consumption.

    Nilsson KW, Sjöberg RL, Wargelius HL, Leppert J, Lindström L and Oreland L

    Centre for Clinical Research, Uppsala University, Central Hospital Västerås, Västerås, Sweden. kent.nilsson@ltv.se

    Aim: To investigate possible interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter, family relations and maltreatment/sexual abuse on adolescent alcohol-related problem behaviour among male adolescents.

    A cross-sectional study of a randomized sample of 66 male individuals from a total population of 16- and 19-year adolescents from a Swedish county. Boys, who volunteered to participate answering an alcohol-related problem/behaviour questionnaire, were investigated with regard to interactions between such problems, family function, maltreatment and MAO-A genotype.

    Measurements: MAO-A genotype, family relations history, history of being maltreated or abused and alcohol-related problem behaviour.

    Findings: Boys with the short (three-repeat) variant of the MAO-A gene, who had been maltreated/abused or came from families with poor relations, showed significantly higher scores of alcohol-related problems. We also found that maltreatment/abuse independently showed the strongest relation to alcohol-related problems among boys in our model.

    Conclusions: The results suggest that both maltreatment and MAO-A genotype may be useful for the understanding of male adolescent alcohol-related problem behaviour.

    Addiction (Abingdon, England) 2007;102;3;389-98

  • Association study between the monoamine oxidase A gene and attention deficit hyperactivity disorder in Taiwanese samples.

    Xu X, Brookes K, Chen CK, Huang YS, Wu YY and Asherson P

    MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. x.xu@iop.kcl.ac.uk

    Background: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable disorder of childhood characterized by inattention, hyperactivity and impulsivity. Molecular genetic and pharmacological studies suggest the involvement of the dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Monoamine oxidase A (MAO-A) encodes an enzyme that degrades biogenic amines, including neurotransmitters such as norepinephrine, dopamine and serotonin. In this study we examined a 30 bp promoter variable number tandem repeat (VNTR) and a functional G/T single nucleotide polymorphism (SNP) at position 941 in exon 8 (941G/T) of MAO-A for association with ADHD in a Taiwanese sample of 212 ADHD probands.

    Methods: Within-family transmission disequilibrium test (TDT) was used to analyse association of MAO-A polymorphisms with ADHD in a Taiwanese population.

    Results: A nominally significant association was found between the G-allele of 941G/T in MAO-A and ADHD (TDT: P = 0.034. OR = 1.57). Haplotype analysis identified increased transmission of a haplotype consisting of the 3-repeat allele of the promoter VNTR and the G-allele of the 941G/T SNP (P = 0.045) to ADHD cases which the strong association with the G-allele drove.

    Conclusion: These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD in the Taiwanese population. These results replicate previously published findings in a Caucasian sample.

    Funded by: Wellcome Trust

    BMC psychiatry 2007;7;10

  • Analysis of monoamine oxidase A promoter polymorphism in mentally retarded individuals.

    Das Bhowmik A, Das M, Sinha S and Mukhopadhyay K

    Psychiatric genetics 2007;17;1;5

  • Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan.

    Wang TJ, Huang SY, Lin WW, Lo HY, Wu PL, Wang YS, Wu YS, Ko HC, Shih JC and Lu RB

    Graduate Institute of Medical Sciences, National Defense Medical Center, Taiwan, ROC; Tsaotun Psychiatric Center, Department of Health, Nantou, Taiwan, ROC.

    Both monoamine oxidase A (MAOA) and dopamine D(2) receptor (DRD2) genes have been considered as candidate genes for antisocial personality disorder with alcoholism (Antisocial ALC) [Parsian, A., 1999. Sequence analysis of exon 8 of MAO-A gene in alcoholics with antisocial personality and normal controls. Genomics. 45, 290-295.; Samochowiec, J., Lesch, K.P., Rottmann, M., Smolka, M., Syagailo, Y.V., Okladnova, O., Rommelspacher, H., Winterer, G., Schmidt, L.G., Sander, T., 1999. Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry. Res. 86, 67-72.; Schmidt, L.vG., Sander, T., Kuhn, S., Smolka, M., Rommelspacher, H., Samochowiec, J., Lesch, K.P., 2000. Different allele distribution of a regulatory MAO-A gene promotor polymorphism in antisocial and anxious-depressive alcoholics. J. Neural .Transm. 107, 681-689.]. However, the association between alcoholism and MAOA or DRD2 gene has not been universally accepted [Lee, J.F., Lu, R.B., Ko, H.C., Chang, F.M., Yin, S.J., Pakstis, A.J., Kidd, K.K., 1999. No association between DRD(2) locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol. Clin. Exp. Res. 23, 592-599.; Lu, R.B., Lin, W.W., Lee, J.F., Ko, H.C., Shih, J.C., 2003. Neither antisocial personality disorder nor antisocial alcoholism association with MAOA gene among Han Chinese males in Taiwan. Alcohol. Clin. Exp. Res. 27, 889-893.]. Since dopamine is metabolized to 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) via monoamine oxidase (MAO) [Westerink, B.H., de Vries, J.B., 1985. On the origin of dopamine and its metabolite in predominantly noradrenergic innervated brain areas. Brain. Res. 330, 164-166.], the interaction between MAOA and DRD2 genes might be related to Antisocial ALC. The present study aimed to determine whether Antisocial ALC might be associated with the possible interactions of DRD2 gene with MAOA gene. Of the 231 Han Chinese subjects who were recruited for the study, 73 participants were diagnosed with Antisocial ALC and 158 subjects were diagnosed with antisocial personality disorder without alcoholism (Antisocial Non-ALC). The DRD2 TaqI A and MAOA-uVNTR (variable number of tandem repeat located upstream) polymorphisms were not found to be associated with Antisocial ALC. However, an association between DRD2 TaqI A polymorphisms and Antisocial ALC was shown only after stratification for the MAOA-uVNTR 4-repeat polymorphism. Additionally, after multiple logistic regressions, we found that, under stratification of MAOA-uVNTR 4-repeat polymorphism and in comparison with the DRD2 A1/A1 genotype as a reference group, the DRD2 A1/A2 genotype has a possible protective effect against alcoholism in individuals with antisocial personality disorder (ASPD). We concluded that the possible interactions between MAOA-uVNTR polymorphism and DRD2 TaqI A polymorphism might be related to Antisocial ALC among Han Chinese men in Taiwan.

    Funded by: NIMH NIH HHS: R01MH37020, R37MH39085

    Progress in neuro-psychopharmacology & biological psychiatry 2007;31;1;108-14

  • Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population.

    Christiansen L, Tan Q, Iachina M, Bathum L, Kruse TA, McGue M and Christensen K

    Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark. lchristiansen@health.sdu.dk

    Background: Depressed mood is a major concern in the elderly, with consequences for morbidity and mortality. Previous studies have demonstrated that genetic factors in depression and subsyndromal depressive symptoms are no less important in the elderly than during other life stages. Variations in genes included in the serotonin system have been suggested as risk factors for various psychiatric disorders but may also serve as candidates for normal variations in mood.

    Methods: This study included 684 elderly Danish twins to investigate the influence of 11 polymorphisms in 7 serotonin system genes on the mean level of depression symptomatology assessed over several years, reflecting individuals' underlying mood level.

    Results: A suggestive association of sequence variations in genes responsible for the synthesis (TPH), recognition (5-HTR2A), and degradation (MAOA) of serotonin with depression symptomatology was found, although the effect was generally restricted to men. We also found that a specific haplotype in VMAT2, the gene encoding the vesicular monoamine transporter, was significantly associated with depression symptoms in men (p= .007).

    Conclusions: These results suggest that variations in genes encoding the components of serotonin metabolism may influence the basic mood level and that different genetic factors may apply in men and women.

    Funded by: NIA NIH HHS: NIA-P01-AG08761

    Biological psychiatry 2007;61;2;223-30

  • Further evidence of MAO-A gene variants associated with bipolar disorder.

    Müller DJ, Serretti A, Sicard T, Tharmalingam S, King N, Artioli P, Mandelli L, Lorenzi C and Kennedy JL

    Department of Psychiatry, Charité University Medicine Berlin, PUK der Charité im SHK, Charité Campus Mitte, Berlin, Germany.

    The aim of this study was to investigate MAOA gene variants in bipolar disorder by using a family-based association approach. The first sample included 331 nuclear families from Western and Central Canada with at least 1 offspring affected with bipolar disorder comprising a total of 1,044 individuals. All subjects were genotyped for MAOA-941T > G and -uVNTR gene variants using PCR techniques. Haplotype TDT was statistically significant (LRS = 12.17; df = 3; P = 0.0068; permutation global significance = 0.00098), with the T-4 haplotype significantly associated with bipolar disorder (OR = 1.63, 95% CI = 1.11-2.37). Single marker analysis evidenced a borderline association for MAOA-941T > G (P = 0.04), but not for the uVNTR. Pooling the Canadian sample with a second previously reported Italian sample genotyped for the uVNTR variant, negative results were obtained as well. No different results were detected when analyzing female subjects separately. In conclusion, our family-based association study gives mild but further support of the involvement of MAOA variants in bipolar disorder.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;1;37-40

  • The association between fibromyalgia and polymorphism of monoamine oxidase A and interleukin-4.

    Su SY, Chen JJ, Lai CC, Chen CM and Tsai FJ

    Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.

    Because fibromyalgia (FM) is often comorbid with anxiety, and monoamine oxidase A (MAOA) was reported to be associated with anxiety, we determine if there is MAOA gene polymorphism associated with FM patients. Moreover, interleukin 4 (IL-4) was found to be an important cytokine participating in the immunologic pathway of T-helper 2 (Th-2) cells, in this study, we search if the genetic polymorphism of IL-4 intron3 could be demonstrated in FM patients. The genotype of sixty-two FM patients was compared with that of control subjects. The polymorphism of IL-4 intron3 variable number of tandem repeats (VNTR) was demonstrated by performing the genomic polymerase chain reaction (PCR) and analyzing the length of PCR product. Furthermore, the MAOA 941 G to T polymorphism was also determined by PCR-RFLP (restriction fragment length polymorphism) analysis. The MAOA 941 position genotype polymorphism between FM and control subjects was found neither statistically different in male (p=0.60) or female (p=0.52), nor total allelic frequency (p=0.52). Similarly, the difference of IL-4 intron3 polymorphism between FM and control was neither existing in genotype (p=0.06), nor allele frequency (p=0.07). The result suggests either the genetic linkage between FM and anxiety or that between FM and immunologic diseases are weak. Accordingly, the MAOA 941 position and IL-4 intron3 polymorphisms are not susceptible markers to predict FM.

    Clinical rheumatology 2007;26;1;12-6

  • A link between monoamine oxidase-A and apoptosis in serum deprived human SH-SY5Y neuroblastoma cells.

    Fitzgerald JC, Ufer C and Billett EE

    School of Biomedical and Natural Sciences, Nottingham Trent University, Nottingham, UK.

    Increased monoamine oxidase (MAO) activity was recently shown to accompany apoptotic cell death of various neuronal cells following growth factor deprivation. Here we show that in serum deprived SH-SY5Y cells, MAO-A mRNA levels and catalytic activities are increased, linked with activation of the apoptotic executioner caspase-3. Importantly, specific inhibition of MAO-A activity resulted in loss of apoptotic cell morphology. Our study indicates that MAO catalytic activity is involved in apoptotic signalling in response to serum withdrawal in neuronal cells.

    Journal of neural transmission (Vienna, Austria : 1996) 2007;114;6;807-10

  • A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.

    Savitz J, van der Merwe L, Solms M and Ramesar R

    Division of Human Genetics, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. savitz@mail.nih.gov

    The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.

    Neuromolecular medicine 2007;9;2;101-16

  • Association between monoamine oxidase A polymorphisms and anger-related personality traits in Korean women.

    Yang JW, Lee SH, Ryu SH, Lee BC, Kim SH, Joe SH, Jung IK, Choi IG and Ham BJ

    Department of Psychiatry, Korean University, Seoul, South Korea.

    It has been suggested that polymorphisms in the monoamine oxidase A (MAO-A) gene are associated with aggressive and impulsive behaviors. In the present study, we investigated the association of the MAO-A variable number of tandem repeat polymorphism in the promoter region (MAO-A uVNTR) with anger-related personality traits. Specifically, MAO-A uVNTR polymorphisms were examined for associations with the State-Trait Anger Expression Inventory (STAXI) scores in 211 normal Korean women. All subjects were assessed using the STAXI and genotyped for MAO-A uVNTR status. The scores on the STAXI subscales differed significantly among the MAO-A uVNTR polymorphism genotypes in terms of anger expression-out (AX-Out) scores. Post hoc comparisons revealed significant differences between the 3/3 and 4/4, and between 3/4 and 4/4 polymorphisms. However, no significant difference was observed in other STAXI subscale scores among these genotypes. Subjects with the high-activity MAO-A uVNTR had significantly higher AX-Out scores than subjects with other genotypes. MAO-A uVNTR polymorphisms may contribute in part to the expression of anger. These findings support the hypothesis that this polymorphism in the MAO-A gene may be associated with anger-related personality traits in Korean women.

    Neuropsychobiology 2007;56;1;19-23

  • Association of MAO-A variant with complicated grief in major depression.

    Kersting A, Kroker K, Horstmann J, Baune BT, Hohoff C, Mortensen LS, Neumann LC, Arolt V and Domschke K

    Department of Psychiatry, University of Munster, Münster, Germany.

    It has been suggested that monoamine oxidase A (MAO-A) activity is involved in the pathogenesis of major depression. Bereavement-related complicated grief significantly increases the risk of major depression and has been shown to be influenced by serotonergic tonus, possibly conferred by MAO-A activity. Complicated grief--whose inclusion in DSM-V as a separate mental disorder is under discussion--has been shown to be a distinct syndrome with symptoms not seen in depression. Therefore, in the present study, genetic variation in the MAO-A gene was investigated for its influence on complicated grief in major depression.

    Methods: Sixty-six unrelated Caucasian patients (41 female, 25 male) with major depression and a history of bereavement were evaluated for complicated grief using the Inventory of Complicated Grief (ICG), the posttraumatic stress reaction after the loss by means of the Impact of Event Scale (IES-R) and further psychopathological measures. Patients were additionally genotyped for the functional variable number tandem repeat (VNTR) in the promoter region of the MAO-A gene.

    Results: The more active longer allele of the MAO-A VNTR was significantly associated with complicated grief in the female subgroup of patients (chi(2) = 9.471, p = 0.002, OR = 9.208, 95% CI 2.129-38.899, Bonferroni-corrected p = 0.012), whereas there was no such effect in male patients. Higher posttraumatic stress reaction was only nominally associated with the more active longer allele of the MAO-A VNTR in the female subgroup of patients (genotypes: chi(2) = 5.939, p = 0.015, OR = 5.333, 95% CI 1.366-20.557, Bonferroni-corrected p = 0.087). No significant associations of MAO-A VNTR with the severity of depressive symptoms (Beck Depression Inventory), anxiety symptoms (Spielberger State-Trait Anxiety Inventory), general mental health (Brief Symptom Inventory), or perceived social support (F-SozU) were found (all p > 0.10).

    Conclusion: The present pilot study for the first time suggests a gender-specific contribution of the more active MAO-A VNTR variant to an increased vulnerability for complicated grief as a potential intermediate phenotype of major depression.

    Neuropsychobiology 2007;56;4;191-6

  • Association study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior.

    Fresan A, Camarena B, Apiquian R, Aguilar A, Urraca N and Nicolini H

    Clinical Research Division, National Institute of Psychiatry Ramón de la Fuente, Mexico City, Mexico.

    Genes involved in dopamine neurotransmission are interesting candidates to be analyzed in schizophrenia and aggressive behavior. Therefore, we analyzed the functional polymorphisms of the dopamine receptor D4 (DRD4) and monoamine oxidase A (MAO-A) genes in a sample of 71 schizophrenic patients assessed with the Overt Aggression Scale to measure aggressive behavior. CLUMP analysis of the DRD4 48-bp repeat-exon III polymorphism in schizophrenic patients showed significant differences between the aggressive behavior and the nonaggressive groups (T1 = 18.77, d.f. = 6, p = 0.0046; T3 = 6.54, p = 0.0195). However, analysis of the promoter polymorphism of the MAO-A gene revealed no significant association between aggressive and nonaggressive patients. Finally, analysis of Overt Aggression Scale dimensions exhibited significant differences for the DRD4 and MAO-A genes. Our preliminary findings suggest that the DRD4 and MAO-A genes may be involved in aggressive schizophrenic patients.

    Neuropsychobiology 2007;55;3-4;171-5

  • Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds.

    Cicchetti D, Rogosch FA and Sturge-Apple ML

    Institute of Child Development and Department of Psychiatry, University of Minnesota, 51 East River Road, Minneapolis, MN 55455, USA.

    Child maltreatment and polymorphisms of the serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) genes were examined in relation to depressive symptomatology. Adolescents (M age = 16.7 years) from low socioeconomic backgrounds with a history of child maltreatment (n = 207) or no such history (n = 132) were interviewed and provided buccal cells for genetic analysis. Gene x environment interactions were observed. Heightened depressive symptoms were found only among extensively maltreated youth with low MAOA activity. Among comparably maltreated youth with high MAOA activity, self-coping strategies related to lower symptoms. Sexual abuse and the 5-HTT short/short genotype predicted higher depression, anxiety, and somatic symptoms. This Gene x Environment interaction was further moderated by MAOA activity level. The results highlight the protective functions of genetic polymorphisms and coping strategies in high risk youth and offer direction for understanding resilience and its promotion from a multiple levels of analysis perspective.

    Funded by: NIDA NIH HHS: DA12903

    Development and psychopathology 2007;19;4;1161-80

  • Monoallelic expression of MAO-A in skin fibroblasts.

    Nordquist N and Oreland L

    Department of Neuroscience, Uppsala University, Uppsala, Sweden. niklas.nordquist@neuro.uu.se

    X chromosome inactivation in mammalian females occurs early in embryonic development and renders most genes on the inactive X chromosome transcriptionally silenced. As a consequence, females will display an X chromosomal parent-of-origin mosaicism with regard to which parental allele that is expressed. Some genes however, escape inactivation and will therefore be expressed from both alleles. In this study we have investigated if the X-linked MAO-A gene have bi- or mono-allelic expression. This information would indicate whether or not MAO-A gene dosage could potentially explain the observed gender differences that show functional connections to the serotonin system, such as aggression and impulsiveness. To investigate the X inactivation status of MAO-A we have used primary clonal cell cultures, on which allelic expression was assessed with RFLP analysis. Our results show that the MAO-A gene has mono-allelic expression in these cells. This could have important implications for understanding traits that display gender differences.

    Journal of neural transmission (Vienna, Austria : 1996) 2007;114;6;713-6

  • Monoamine oxidases: activities, genotypes and the shaping of behaviour.

    Oreland L, Nilsson K, Damberg M and Hallman J

    Department of Neuroscience, Uppsala University, Uppsala, Sweden. lars.oreland@neuro.uu.se

    The importance of an interaction between environment and biological factors for the expression for a particular behaviour is illustrated by results from a series of adolescents in which effects of platelet MAO activity and psychosocial environment on criminality was investigated. In a favourable environment platelet MAO-B activity was not associated with criminality, while a very strong association was found in adolescents from a bad psychosocial environment. Essentially similar findings were obtained when a MAO-A promoter polymorphism was analysed instead of platelet MAO-B activity. In boys, presence of the low functioning allele seemed to be protective against criminal activity in combination with a good environment, while it predisposed for criminality in a bad psycho-social environment. In girls, instead, homozygosity for the high activity MAO-A allele interacted with environment to predict criminality. Possible mechanisms underlying the role of monoamine oxidases for behaviour are discussed.

    Journal of neural transmission (Vienna, Austria : 1996) 2007;114;6;817-22

  • Deficient expression of monoamine oxidase A in the endometrium is associated with implantation failure in women participating as recipients in oocyte donation.

    Henriquez S, Tapia A, Quezada M, Vargas M, Cardenas H, Rios M, Salvatierra AM, Croxatto H, Orihuela P, Zegers-Hochschild F, Munroe DJ and Velasquez L

    Laboratorio de Inmunología de la Reproducción, Universidad de Santiago de Chile.

    Successful implantation depends both on the quality of the embryo and on the endometrial receptivity. The latter depends on progesterone-induced changes in gene expression, a process that has been characterized by microarray analysis. One of the genes whose transcription appears to be enhanced during the receptive period is monoamine oxidase A (MAO-A). Our first objective was to confirm the increased expression of MAO-A in the endometrium during the receptive phase of spontaneous normal cycles using real time PCR and immunofluorescence. The second objective was to examine the endometrial expression of MAO-A during the receptive phase induced by exogenous estradiol (E(2)) and progesterone in patients whose endometrium was shown to have been either receptive or non-receptive to embryo implantation in repeated cycles of oocyte donation. Results showed that MAO-A transcript levels increased between the pre-receptive (LH+3) and receptive phase (LH+7) in all spontaneous cycles examined, with a median increase of 25-fold. Immunofluorescent labelling demonstrated MAO-A localization to the glandular and luminal epithelium with an increasing positive score between LH+3 and LH+7. Conversely, prior failure of embryo implantation was associated with a 29-fold decrease in MAO-A mRNA levels and a substantial reduction in MAO-A protein immunofluorescent label score. These results show a strong association between endometrial receptivity and MAO-A expression in the endometrial epithelium, suggesting an important role for this enzyme in normal implantation.

    Funded by: NCI NIH HHS: N01-CO-12400

    Molecular human reproduction 2006;12;12;749-54

  • Family-based case-control study of MAOA and MAOB polymorphisms in Parkinson disease.

    Kang SJ, Scott WK, Li YJ, Hauser MA, van der Walt JM, Fujiwara K, Mayhew GM, West SG, Vance JM and Martin ER

    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.

    Monoamine oxidase (MAO) is an enzyme regulating metabolism of neurotransmitters such as dopamine. Two distinct forms of enzyme, encoded by genes MAOA and MAOB located on the X chromosome, have been considered as possible factors in the pathogenesis of Parkinson disease (PD). Previous association studies of PD and MAO genes reported inconsistent results. In this study, we used a large family-based data set to test associations between MAO genes and a risk of PD. The data set includes 298 female discordant sibpairs and 348 male discordant sibpairs. For this study, all subjects analyzed were white and families with known parkin mutations were removed. We analyzed 15 single nucleotide polymorphisms (SNPs) and a dinucleotide repeat marker in the MAO genes. Association was found with the intron 13 SNP of MAOB in the female subset (P = 0.02). No significant association was found in the male subset. Our results add to the evidence of involvement of MAOB in PD and suggest that the effect may be stronger in women.

    Funded by: NINDS NIH HHS: NS051355, NS39764

    Movement disorders : official journal of the Movement Disorder Society 2006;21;12;2175-80

  • The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males.

    Rosenberg S, Templeton AR, Feigin PD, Lancet D, Beckmann JS, Selig S, Hamer DH and Skorecki K

    Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel. rozenber@tx.technion.ac.il

    Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioural traits in normal individuals has been examined. DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioural traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 ("straightforwardness") facet with common allelic variants at the promoter VNTR. Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioural traits in normal males may be very specific. In contrast, several traits of the C ("conscientiousness") axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioural attribute of "straightforwardness", while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to "conscientiousness". This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioural traits.

    Human genetics 2006;120;4;447-59

  • Serotonin transporter, tryptophan hydroxylase, and monoamine oxidase A gene polymorphisms in premenstrual dysphoric disorder.

    Magnay JL, Ismail KM, Chapman G, Cioni L, Jones PW and O'Brien S

    Institute of Science and Technology in Medicine, Keele University, Staffordshire, UK. j.l.magnay@bemp.keele.co.uk

    Objective: The purpose of this study was to investigate whether common polymorphisms of key genes that control the serotonin (5-hydroxytryptamine) pathway are associated with premenstrual dysphoric disorder.

    The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range, 27-46 years; mean age, 37.7 years) and 52 healthy control subjects (age range, 22-48 years; mean age, 36.2 years). Eight polymorphisms that encode the 5-hydroxytryptamine transporter (LPR, VNTR-2, and 3' UTR G/T), tryptophan hydroxylase 1 (TPH1 G-6526A, G-5806T, and A218C), and monoamine oxidase A (monoamine oxidase A promoter VNTR-1 and exon 8 Fnu 4H1) were genotyped. Genotype and allelic frequencies were analyzed by chi-square test and stepwise logistic regression analysis.

    Results: There was no significant association between any genotype and clinical category and no significant allelic distribution profiles in either the premenstrual dysphoric disorder group or the control group.

    Conclusion: These findings do not support a major role for common 5-hydroxytryptamine transporter, TPH1, and monoamine oxidase A polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder.

    American journal of obstetrics and gynecology 2006;195;5;1254-9

  • Childhood maltreatment, subsequent antisocial behavior, and the role of monoamine oxidase A genotype.

    Huizinga D, Haberstick BC, Smolen A, Menard S, Young SE, Corley RP, Stallings MC, Grotpeter J and Hewitt JK

    Institute of Behavioral Science, University of Colorado, Boulder, 80303, USA. huizinga@colorado.edu

    Background: A functional promoter polymorphism in monoamine oxidase A (MAOA) has been implicated as a moderating factor in the relationship between childhood maltreatment and later adolescent and adult antisocial behavior. Despite wide interest in this hypothesis, results remain mixed from the few attempts at replication.

    Methods: Regression-based analyses were conducted to test for a genotype-environment interaction using self-reported physical abuse and MAOA genotype to predict later antisocial behavior and arrests for violence by participants in the National Youth Survey Family Study. We also examined the interaction using a measure of violent victimization. The analysis sample included 277 Caucasian male respondents, aged 11-15 in 1976, who provided buccal swab DNA samples and who were successfully genotyped for the variable number tandem repeat (VNTR) in the MAOA promoter using polymerase chain reaction.

    Results: Maltreatment by a parent during adolescence was a risk factor for adolescent and adult antisocial and violence related behavioral problems. Tests for the main effect of MAOA and a MAOA-maltreatment interaction were nonsignificant. Similar results were obtained using the measure of adolescent violent victimization.

    Conclusions: Findings from this general population sample could not confirm the hypothesis that MAOA moderates the relationship between adolescent maltreatment and adolescent or adult antisocial behavior.

    Funded by: NIAAA NIH HHS: AA011949, AA07646; NICHD NIH HHS: HD07089; NIDA NIH HHS: DA11015, DA12845; NIMH NIH HHS: MH01865

    Biological psychiatry 2006;60;7;677-83

  • MAOA and the "cycle of violence:" childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior.

    Widom CS and Brzustowicz LM

    Department of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, 07103, USA. widomca@umdnj.edu

    Background: Two recent studies with white males have shown that genotypes associated with high levels of monamine oxidase A (MAOA) protect against the impact of childhood maltreatment and adversity on the development of antisocial behavior and conduct disorder.

    Methods: Participants in a prospective cohort design study involving court substantiated cases of child abuse and neglect and a matched comparison group were followed up into adulthood and interviewed (N = 802). Eighty-two percent consented to provide blood and 631 gave permission for DNA extraction and analyses. A composite index of violent and antisocial behavior (VASB) was created based on arrest, self-report, and diagnostic information.

    Results: No main effect was found for the relationship between MAOA genotype and VASB. Genotypes associated with high levels of MAOA activity buffered abused and neglected whites from increased risk of becoming violent and/or antisocial in later life. This protective effect was not found for non-white abused and neglected individuals.

    Conclusions: Possible explanations for this differential effect for whites and non-whites include differences in contextual factors (e.g., environmental stressors) and a question of the suitability of using the MAOA promoter VNTR polymorphism as a proxy for MAOA levels in non-white populations.

    Funded by: NIAAA NIH HHS: AA09238; NICHD NIH HHS: HD40774; NIDA NIH HHS: DA017842, DA10060; NIMH NIH HHS: MH49467, MH58386

    Biological psychiatry 2006;60;7;684-9

  • The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

    Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Anney R, Aneey R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink M, Arnold R, Boer F, Buschgens C, Butler L, Christiansen H, Feldman L, Fleischman K, Fliers E, Howe-Forbes R, Goldfarb A, Heise A, Gabriëls I, Korn-Lubetzki I, Johansson L, Marco R, Medad S, Minderaa R, Mulas F, Müller U, Mulligan A, Rabin K, Rommelse N, Sethna V, Sorohan J, Uebel H, Psychogiou L, Weeks A, Barrett R, Craig I, Banaschewski T, Sonuga-Barke E, Eisenberg J, Kuntsi J, Manor I, McGuffin P, Miranda A, Oades RD, Plomin R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Taylor E, Thompson M, Faraone SV and Asherson P

    MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, London, UK.

    Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

    Funded by: Medical Research Council: G0300189, G0501329, G19/2; NIMH NIH HHS: R01MH62873

    Molecular psychiatry 2006;11;10;934-53

  • Association between monoamine oxidase gene polymorphisms and smoking behaviour in Chinese males.

    Jin Y, Chen D, Hu Y, Guo S, Sun H, Lu A, Zhang X and Li L

    Peking University Stem Cell Research Center, Beijing Anding Hospital Affiliated Capital University of Medical Sciences, China.

    Monoamine oxidase (MAO) is a critical metabolic enzyme of dopamine, which is a key neurotransmitter of the mesolimbic reward pathway in the human brain. Consequently, the gene encoding MAO is an important candidate gene in the genetics of smoking behaviour. We investigated the association between MAOA polymorphisms (a VNTR polymorphism and an EcoRV polymorphism) and smoking status. A community-based cross-sectional study was conducted with 203 current smoking subjects and 168 non-current smoking subjects in Beijing, China. Genotyping for these polymorphisms was performed using PCR and restriction fragment length polymorphism. Multiple logistic regression models were used to analyse the association of MAOA gene polymorphisms with smoking status. We found that individuals with the 1460T/O genotype had a significantly increased the risk of smoking compared to those with 1460C/O. The adjusted odds ratios (aORs) were 3.2 (95% CI 2.0-5.2) in current vs. non-current smokers group, 1.7 (95% CI 1.1-2.8) in ever vs. never smokers group, 2.5 (95% CI 1.4-4.3) in current vs. never smokers group, and 5.3 (95% CI 2.5-11.2) in current vs. former smokers group respectively. We also found that individuals with the 3-repeat genotype of the VNTR polymorphism had a significantly increased risk of smoking significantly compared to those with the 4-repeat genotype. The aORs were 2.0 (95% CI 1.0-4.1) in the current vs. former smokers group, and 1.9 (95% CI 1.0-3.6) in the nicotine dependent vs. non-nicotine dependent group respectively. Moreover, MAOA gene haplotypes were associated significantly with nicotine dependence in every group. In conclusion, there is an important association between MAOA polymorphisms and smoking status, suggesting a possible role of MAOA gene variants in nicotine dependence.

    The international journal of neuropsychopharmacology 2006;9;5;557-64

  • MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

    Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW and Moffitt TE

    Department of Psychology, Yale University, New Haven, CT 06520, USA. julia.kim-cohen@yale.edu

    Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

    Funded by: Medical Research Council: G0100527, G9806489; NIMH NIH HHS: MH45070, MH49414

    Molecular psychiatry 2006;11;10;903-13

  • Monoallelic expression of MAOA in skin fibroblasts.

    Nordquist N and Oreland L

    Department of Neuroscience, Uppsala University, Uppsala, Sweden. niklas.nordquist@neuro.uu.se

    X chromosome inactivation in mammalian females occurs early in embryonic development and renders most genes on the inactive X chromosome transcriptionally silenced. As a consequence, females will display an X chromosomal parent-of-origin mosaiscism with regard to which parental allele that is expressed. Some genes, however, escape inactivation and will therefore be expressed from both alleles. In this study, we have investigated if the X-linked MAO-A gene has bi- or mono-allelic expression. This information would indicate whether or not MAO-A gene dosage could potentially explain the observed gender differences that show functional connections to the serotonin system, such as aggression, and impulsiveness. To investigate the X inactivation status of MAO-A we have used primary clonal cell cultures, on which allelic expression was assessed with RFLP analysis. Our results show that the MAO-A gene has mono-allelic expression in these cells. This could have important implications for understanding traits that display gender differences.

    Biochemical and biophysical research communications 2006;348;2;763-7

  • MAOA promoter polymorphism and attention deficit hyperactivity disorder (ADHD) in indian children.

    Das M, Bhowmik AD, Sinha S, Chattopadhyay A, Chaudhuri K, Singh M and Mukhopadhyay K

    Manovikas Biomedical Research and Diagnostic Centre, E.M. Bypass, Kolkata, India.

    Attention deficit hyperactivity disorder (ADHD) is a highly disabling, early onset childhood neurobehavioral disorder with a higher occurrence in boys as compared to girls. Pharmacological and molecular genetic studies have revealed the influence of dopaminergic and serotonergic systems in the etiology of the disorder. Monoamine oxidase A (MAOA) is a mitochondrial enzyme that regulates the dopaminergic signals in the pre-synaptic region. Polymorphism in the promoter region of the MAOA gene, which comprises of 30 bp repeats with repeat number varying between 2.5, 3.5, 4.5, and 5.5, has been shown to be associated with various neurobehavioral disorders including ADHD. This is the first study on Indian ADHD cases to validate an association between transmission of MAOA promoter polymorphism and risk of ADHD. We have analyzed the MAOA promoter polymorphism in a group of ADHD probands, their parents and ethnically matched controls by UNPHASED. Our findings indicate significant difference in the frequency of 3.5 repeat allele (P = 0.02) between cases and controls and preferential transmission of the short allele (3.5 repeat) from mothers to male ADHD probands (P = 0.005). We conclude that the short 3.5 repeat allele of the MAOA-u VNTR is probably associated with ADHD in our population and could be the reason for making boys prone to ADHD as compared to girls.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;6;637-42

  • Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain: dissection of epigenetic and genetic factors.

    Pinsonneault JK, Papp AC and Sadée W

    Department of Pharmacology, Program in Pharmacogenomics, College of Medicine and Public Health, The Ohio State University, Columbus 43210, USA. pinsonneault.2@osu.edu

    A pVNTR repeat polymorphism located in the promoter region of the X-linked MAOA gene has been associated with mental disorders. To explore the effect of polymorphisms and epigenetic factors on mRNA expression, we have measured allelic expression imbalance (AEI) in female human brain tissue, employing two frequent marker single nucleotide polymorphisms (SNPs) in exon 8 (T890G) and exon 14 (C1409T) of MAOA. This approach compares one allele against the other in the same subject. AEI ratios ranged from 0.3 to 4 in prefrontal cortex, demonstrating the presence of strong cis-acting factors in mRNA expression. Analysis of CpG methylation in the MAOA promoter region revealed substantial methylation in females but not in males. MAOA methylation ratios for the three- and four-repeat pVNTR alleles of MAOA did not correlate with X-chromosome inactivation ratios, determined at the X-linked androgen receptor locus, suggesting an alternative process of dosage compensation in females. The extent of allelic MAOA methylation was highly variable and correlated with AEI (R2=0.5 and 0.7 at two CpG loci), indicating that CpG methylation regulates gene expression. Genetic factors appeared also to contribute to the AEI ratios. Genotyping of 13 MAOA polymorphisms in female subjects showed strong association with a haplotype block spanning from the pVNTR to the marker SNP. Therefore, allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate biogenic amine tone in the CNS.

    Funded by: NIDA NIH HHS: R21 DA108744

    Human molecular genetics 2006;15;17;2636-49

  • A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index.

    Ducci F, Newman TK, Funt S, Brown GL, Virkkunen M and Goldman D

    Laboratory of Neurogenetics, NIAAA, NIH, Rockville, MD 20852, USA. ducci@mail.nih.gov

    Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

    Molecular psychiatry 2006;11;9;858-66

  • A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse.

    Cevoli S, Mochi M, Scapoli C, Marzocchi N, Pierangeli G, Pini LA, Cortelli P and Montagna P

    Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy.

    To assess the role of dopamine metabolism-related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono-amino-oxidase A (MAOA) and cathecol-O-methyl-transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.

    European journal of neurology 2006;13;9;1009-13

  • [Association of functional genes polymorphisms of key enzymes in the metabolism of biogenic amines with paranoid schizophrenia susceptibility and the influence of these polymorphisms on PANSS results in antipsychotic treatment].

    Tybura P, Grzywacz A, Syrek S, Parus M and Samochowiec J

    Klinika Psychiatrii Pomorskiej AM w Szczecinie.

    Aim: The genetic components of the schizophrenia susceptibility are calculated as being 50%. We evaluated the frequency of alleles and genotypes of COMT and MAO-A genes polymorphisms in patients with schizophrenia and in the healthy population. We searched for the associations between genotypes and PANSS results among patients in a three month antipsychotic therapy.

    Method: The study comprised 72 unrelated patients who met ICD-10 criteria for schizophrenia, and 187 unrelated healthy controls. The analysis of COMT and MAO-A genes polymorphisms were performed using the polymerase chain reaction technique (RFLP-restriction fragments length polymorphism and VNTR-variable number tandem repeats). The severity of psychopathological symptoms was measured by the PANSS (Positive and Negative Schizophrenia Scale).

    Results: We did not find an association between the genotype of COMT and MAO-A genes polymorphisms and schizophrenia. We found statistically significant different allele distribution in MAO gene polymorphism: alleles with three tandem repeats in the promoter region were more frequent among females with schizophrenia. We did not find any association between the genotype of COMT and MAO-A genes polymorphisms and PANSS results in any time periods. Due to a small number of patients in this study the obtained results should be regarded as preliminary.

    Psychiatria polska 2006;40;5;913-23

  • Genetically increased risk of sleep disruption in Alzheimer's disease.

    Craig D, Hart DJ and Passmore AP

    Department of Geriatric Medicine, Queen's University of Belfast, Northern Ireland, United Kingdom. david.craig@qub.ac.uk

    To investigate the role of a monoamine A oxidase promoter polymorphism in sleep disruption in Alzheimer's disease (AD).

    Design: A case-control association analysis.

    Setting: Sleep disturbance in AD is common, is extremely stressful for caregivers, and increases the risk of institutionalisation. It remains unclear why only some patients develop sleep disturbance; neuropathologic changes of AD are not typically seen in the areas of the brain responsible for sleep. We hypothesized that the risk of sleep disturbance is, at least in part, influenced by the availability of serotonin used for melatonin synthesis secondary to polymorphic variation at the enzyme monoamine oxidase A (MAO-A).

    Patients: Patients with AD diagnosed according to standard criteria.

    Interventions: Data were collected using the Sleep domain of the Neuropsychiatric Inventory with Caregiver Distress. Patients' cognition and function were assessed using the Mini-Mental State Examination and the Functional Assessment Staging. Genotyping of apolipoprotein E (APOE) and of the 30 bp variable number tandem repeat of the MAO-A promoter was by standard methods.

    Of 426 patients surveyed, 54% experienced sleep disturbance. We found that the high-activity 4-repeat allele of the MAO-A VNTR promoter polymorphism confers increased susceptibility to sleep disturbance (p = .008). A quantitative sleep disturbance score was significantly higher in the patients possessing MAO-A 4-repeat allele genotypes. APOE had no influence on the development of an altered sleep phenotype.

    Conclusions: We conclude that sleep disturbance in AD is common and distressing and is associated with genetic variation at MAO-A.

    Sleep 2006;29;8;1003-7

  • Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1.

    Ou XM, Chen K and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California 90033, USA.

    Monoamine oxidase (MAO) A is a key enzyme for the degradation of neurotransmitters serotonin, norepinephrine, and dopamine. There are three consensus glucocorticoid/androgen response elements and four Sp1-binding sites in the human monoamine oxidase A 2-kb promoter. A novel transcription factor R1 (RAM2/CDCA7L) interacts with Sp1-binding sites and represses MAO A gene expression. Luciferase assays show that glucocorticoid (dexamethasone) and androgen (R1881) increase MAO A promoter and catalytic activities in human neuroblastoma and glioblastoma cells. Gel-shift analysis demonstrates that glucocorticoid/androgen receptors interact directly with the third glucocorticoid/androgen response element. Glucocorticoid/androgen receptors also interact with Sp1-binding sites indirectly via transcription factor Sp1. In addition, dexamethasone induces R1 translocation from the cytosol to the nucleus in a time-dependent manner in both the neuroblastoma and wild-type UW228 cell lines but not in R1 knock-down UW228 cells. In summary, this study shows that glucocorticoid enhances monoamine oxidase A gene expression by 1) regulation of R1 translocation; 2) direct interaction of the glucocorticoid receptor with the third glucocorticoid/androgen response element; and 3) indirect interaction of glucocorticoid receptor with the Sp1 or R1 transcription factor on Sp1-binding sites of the MAO A promoter. Androgen also up-regulates MAO A gene expression by direct interaction of androgen receptor with the third glucocorticoid/androgen response element. Androgen receptor indirectly interacts with the Sp1, but not R1 transcription factor, on Sp1-binding sites. This study provides new insights on the differential regulation of MAO A by glucocorticoid and androgen.

    Funded by: NIMH NIH HHS: R01 MH67968, R37 MH39085

    The Journal of biological chemistry 2006;281;30;21512-25

  • Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans.

    Kim H, Lee H, Rowan J, Brahim J and Dionne RA

    National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA. kimhy@mail.nih.gov

    Background: Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans.

    Results: Variations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene (SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample.

    Conclusion: These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.

    Funded by: Intramural NIH HHS

    Molecular pain 2006;2;24

  • Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway.

    Ou XM, Chen K and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.

    Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2/CDCA7L/JPO2) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and R1 in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.

    Funded by: NIMH NIH HHS: R01 MH067968, R01 MH67968, R37 MH039085, R37 MH39085

    Proceedings of the National Academy of Sciences of the United States of America 2006;103;29;10923-8

  • Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia.

    De Luca V, Tharmalingam S, Müller DJ, Wong G, de Bartolomeis A and Kennedy JL

    Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street R-30, Toronto, Ontario, Canada M5T 1R8. Vincenzo_Deluca@camh.net

    A large body of evidence suggests that suicidal behavior is associated with altered noradrenergic neurotransmission. Norepinephrine is degraded by monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). Our hypothesis is that the genes encoding MAOA and COMT might contain genetic variants conferring increased risk for suicidal behavior in schizophrenia and that both genes may interact each other. In order to test this hypothesis, we genotyped the promoter VNTR polymorphism in the MAOA gene and three COMT polymorphisms: -287A>G, Val/Met and 3'UTR C Ins/Del in a cohort of 270 schizophrenics in which 92 attempted suicide. No association between suicide attempt and the MAOA VNTR (P = 0.382), Val108/158Met (P = 0.788) or -287A>G (P = 0.420) polymorphisms was found, however, a slight significant finding was found for 3'UTR polymorphism (P = 0.050). Haplotype analysis for COMT gene revealed no association between suicide attempts and haplotype distribution (P = 0.451). As we tested for epistasis between MAOA VNTR and COMT Val/Met, we found no significant interaction in conferring risk for suicide attempts (P = 0.545). These results suggest that epistasis between MAOA and COMT genes may not influence suicidal behavior in patients with schizophrenia.

    Brain research 2006;1097;1;26-30

  • An association study of catechol-O-methyltransferase and monoamine oxidase A polymorphisms and personality traits in Koreans.

    Kim SJ, Kim YS, Kim SY, Lee HS and Kim CH

    Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, South Korea.

    Catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) are both involved in the degradation of various biogenic amines which have been hypothesized to have a relationship with personality traits. The present study investigated the possible relationships between the genotypes of COMT Val158Met and MAOA-uVNTR polymorphisms and personality traits measured by the Temperament and Character Inventory (TCI). We recruited 286 normal, unrelated Korean subjects (138 males and 148 females). There were no associations between the COMT Val158Met genotypes or the TCI subscales in the male subjects. However, a significant correlation was observed between the COMT genotype and harm avoidance (HA, F=6.0, p=0.003) in females. Post hoc analyses showed that the subjects with the Met/Met genotype had the lowest mean HA (HA=13.8+/-5.7, p=0.02), Val/Met group had an intermediate mean HA score (HA=16.3+/-7.0, p=0.02), and Val/Val group had the highest mean HA value (HA=19.6+/-7.0, p=0.02). There were no associations between the MAOA-uVNTR and the TCI subscales in either the male or female subjects. These results suggest that genetic variants of the COMT Val158Met gene may play a role in HA in Korean females but not in males.

    Neuroscience letters 2006;401;1-2;154-8

  • Interaction between MAO-A genotype and maltreatment in the risk for conduct disorder: failure to confirm in adolescent patients.

    Young SE, Smolen A, Hewitt JK, Haberstick BC, Stallings MC, Corley RP and Crowley TJ

    Institute for Behavioral Genetics, UCB 447, University of Colorado, Boulder, CO 80301, USA.

    Objective: Childhood maltreatment is a potent risk factor for subsequent aggressive and criminal behavior. A recent study suggested that the relationship between maltreatment and antisocial behavior may be moderated by a genetic vulnerability conferred by a functional polymorphism in the MAO-A gene. The authors investigated whether these findings would generalize to a clinical cohort of adolescents, examining whether there was a stronger association between maltreatment and conduct disorder severity in patients carrying the low MAO-A activity allele.

    Method: Male adolescent patients (N=247) entering residential or intensive day treatment for persistent conduct and substance use problems were examined. Conduct disorder severity was indexed by a lifetime count of DSM-IV criteria obtained through structured psychiatric interviews. Maltreatment scores were derived from summing neglect and abuse events reported to have occurred before age 11.

    Results: Neglect, verbal/psychological abuse, physical abuse, and sexual abuse were prevalent among patients. Although level of maltreatment and lifetime conduct disorder symptoms were significantly correlated, no genetic-environmental interaction with genotype for maltreatment was found.

    Conclusion: The results of the current study do not support the hypothesis that a polymorphism in the gene encoding MAO-A contributes to the genetic risk for conduct disorder.

    Funded by: NIDA NIH HHS: DA-06941, DA-09842, DA-11015, DA-12845, P60 DA011015, R01 DA009842, R01 DA012845, R37 DA009842; NIMH NIH HHS: MH-01865

    The American journal of psychiatry 2006;163;6;1019-25

  • Obesity is associated with genetic variants that alter dopamine availability.

    Need AC, Ahmadi KR, Spector TD and Goldstein DB

    Department of Biology, University College London, The Darwin Building, Gower Street, London WC1E 6BT.

    Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI > or = 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA:chi2= 15.45, p = 0.004; MAOB:chi2= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype'--low activity genotypes at both the MAOA and MAOB loci--shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.

    Funded by: Wellcome Trust

    Annals of human genetics 2006;70;Pt 3;293-303

  • MAOA-uVNTR polymorphism in a Brazilian sample: further support for the association with impulsive behaviors and alcohol dependence.

    Contini V, Marques FZ, Garcia CE, Hutz MH and Bau CH

    Department of Genetics, Institute of Biosciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

    The enzyme monoamine oxidase A (MAO A) plays an important role in the metabolism of neurotransmitters. The MAOA gene presents several polymorphisms, including a 30-bp VNTR in the promoter region (MAOA-uVNTR). Alleles with 3.5 and 4 repeats are 2-10 times more efficient than the 3-repeat allele. Several studies have shown an association between the 3-repeat allele and a cluster of externalizing behaviors including alcoholism, antisocial personality, and impulsivity. The objective of the present study is to replicate in a different culture the associations between the MAOA-uVNTR with alcoholism and other phenotypes. The sample comprises 125 Brazilian alcoholics of European descent and 235 controls. The results suggest that the 3-repeat allele is associated to: (1) alcohol dependence (P < 0.05); (2) an earlier onset of alcoholism (P < 0.01); (3) comorbid drug abuse among alcoholics (P < 0.05); and (4) a higher number of antisocial symptoms (P < 0.02). Our results confirmed previous reports showing an association of the low activity 3-repeat allele of MAOA-uVNTR polymorphism with substance dependence and impulsive/antisocial behaviors. These findings in a different culture further support the influence of the MAOA-uVNTR in psychiatric disorders.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;3;305-8

  • Interaction of serotonergic and noradrenergic gene variants in panic disorder.

    Freitag CM, Domschke K, Rothe C, Lee YJ, Hohoff C, Gutknecht L, Sand P, Fimmers R, Lesch KP and Deckert J

    Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany. christine.freitag@uniklinikum-saarland.de

    Objective: Panic disorder is an anxiety disorder with an estimated heritability of 48%. Associations findings have been obtained with candidate genes from both serotonergic and noradrenergic pathways including regulatory and coding variants of the serotonin receptor 1A gene, the monoamine oxidase A gene, the catechol-O-methyltransferase gene and the norepinephrine transporter gene.

    Methods: In the present study, an analysis of interactions between the functional serotonin receptor 1A polymorphism, the norepinephrine transporter variants and the other respective polymorphisms of the above-mentioned genes is reported. The analysis is based on genotype results from 115 cases and 115 age and sex-matched controls.

    Results: A nominally significant (P=0.04) interaction between the serotonin receptor 1A and the catechol-O-methyltransferase polymorphisms was observed. Stratified analysis revealed that the odds ratio of each polymorphism was highest in the presence of the low-risk genotype(s) of the other polymorphism and low in the presence of the high-risk genotype(s) of the other polymorphism.

    Conclusions: This is the first possible interaction of genetic variations in panic disorder that has been observed. As the sample size was small and no adjustment for multiple testing was made, the assessment of the interacting risk alleles needs replication in a larger sample with higher power.

    Psychiatric genetics 2006;16;2;59-65

  • Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants.

    Shiraishi H, Suzuki A, Fukasawa T, Aoshima T, Ujiie Y, Ishii G and Otani K

    Department of Psychiatry, Yamagata University School of Medicine, Yamagata City, Japan.

    It has been suggested that monoamine oxidase A plays an important role in the characterization of personality. Previous studies on the association between the polymorphism of variable number tandem repeat in the promoter region of the monoamine oxidase A gene and personality traits have, however, been unproductive. In the present study, the association between the monoamine oxidase A variable number tandem repeat polymorphism and personality traits assessed by the Temperament and Character Inventory was examined in 324 Japanese volunteers without psychiatric disorders. The low activity allele with three repeats (allele 3) and high activity allele with four repeats (allele 4) were determined by a polymerase chain reaction method. The carriers of allele 3 in males and the homozygotes of allele 3 in females were classified as the low activity group, the heterozygotes of alleles 3 and 4 in females as the medium activity group, and the carriers of allele 4 in males and the homozygotes of allele 4 in females as the high activity group. One-way analysis of variance showed that the scores of novelty seeking (P=0.006) and reward dependence (P=0.013) were significantly higher in the high activity group than in the low activity group. Multiple regression analysis demonstrated that the excess in the high activity allele was significantly associated with higher scores of novelty seeking (P=0.004) and reward dependence (P=0.003). The present study thus suggests that the monoamine oxidase A variable number tandem repeat polymorphism affects novelty seeking and reward dependence in healthy study participants.

    Psychiatric genetics 2006;16;2;55-8

  • Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue.

    Smith AK, White PD, Aslakson E, Vollmer-Conna U and Rajeevan MS

    Centers for Disease Control and Prevention, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, 1600 Clifton Road, MSG41, Atlanta, GA 30333, USA.

    Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing fatigue that is not alleviated by rest, causes substantial reduction in activities and is accompanied by a variety of symptoms. Its unknown etiology may reflect that CFS is heterogeneous. Latent class analyses of symptoms and physiological systems were used to delineate subgroups within a population-based sample of fatigued and nonfatigued subjects [1] . This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated by comparing each of the five ill classes (Class 1, n = 33; Class 3, n = 22; Class 4, n = 22; Class 5, n = 17; Class 6, n = 11) of fatigued subjects with subjects defined as well (Class 2, n = 35). Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions.

    Pharmacogenomics 2006;7;3;387-94

  • Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase, monoamine oxidase A, and catechol-O-methyltransferase genes.

    Tochigi M, Otowa T, Hibino H, Kato C, Otani T, Umekage T, Utsumi T, Kato N and Sasaki T

    Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan.

    Several molecular genetic studies have been conducted with regard to the association between catecholamine-related genes and personality traits. However, the results of replication studies did not always coincide. One of the possible reasons may be that the effect exerted by the individual gene is small. In the present study, we investigated the association between personality traits and systematic combination of functional polymorphisms in three genes that regulate the metabolism of catecholamines, namely, tyrosine hydroxylase (TH), monoamine oxidase A (MAOA), and catechol-O-methyltransferase (COMT). The (TCAT)n repeat in the TH gene, the promoter variable number tandem repeat (VNTR) in the MAOA gene, and Val158Met in the COMT gene were genotyped in 256 healthy Japanese volunteers. Personality traits were evaluated using the NEO Personality Inventory-Revised (NEO PI-R). As a result, the score for Neuroticism increased, and those for Extraversion and Conscientiousness decreased according to the degree of functional polymorphic change, i.e., the lower synthesis/higher catalysis of catecholamines. A statistically significant difference was observed in the change of Extraversion (p=0.04, after Bonferroni correction). These results may provide evidence for the association between metabolic change of catecholamines and personality traits, which may be due to the additive effect of the three genes.

    Neuroscience research 2006;54;3;180-5

  • Monoamine oxidase-a genetic variations influence brain activity associated with inhibitory control: new insight into the neural correlates of impulsivity.

    Passamonti L, Fera F, Magariello A, Cerasa A, Gioia MC, Muglia M, Nicoletti G, Gallo O, Provinciali L and Quattrone A

    Neurology Unit, Department of Neurosciences, University Politecnica delle Marche, Ancona, Italy.

    Background: Previous evidence has shown that genetic variations in the serotonergic system contribute to individual differences in personality traits germane to impulse control. The monoamine oxidase-A (MAO-A) gene, coding for an enzyme primarily involved in serotonin and noradrenaline catabolism, presents a well-characterized functional polymorphism consisting of a variable number of tandem repeats in the promoter region, with high-activity and low-activity variants. High-activity allele carriers have higher enzyme expression, lower amine concentration, and present higher scores on behavioral measures of impulsivity than low-activity allele carriers.

    Methods: We studied the relationship of this polymorphism to brain activity elicited by a response inhibition task (Go/NoGo task), using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging in 24 healthy men.

    Results: Direct comparison between groups revealed a greater BOLD response in the right ventrolateral prefrontal cortex (Brodmann's area [BA] 45/47) in high-activity allele carriers, whereas a greater response in the right superior parietal cortex (BA 7) and bilateral extrastriate cortex (BA 18) was found in low-activity allele carriers.

    Conclusions: These data suggest that a specific genetic variation involving serotonergic catabolism can modulate BOLD response associated with human impulsivity.

    Funded by: Medical Research Council: MC_U105579214

    Biological psychiatry 2006;59;4;334-40

  • Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity.

    Nilsson KW, Sjöberg RL, Damberg M, Leppert J, Ohrvik J, Alm PO, Lindström L and Oreland L

    Centre for Clinical Research, Uppsala University, Central Hospital Västerås, S-721 89 Västerås, Sweden. kent.nilsson@ltvastmanland.se

    Background: A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity.

    Methods: A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of Västmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior.

    Results: The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A-gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%.

    Conclusions: The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.

    Biological psychiatry 2006;59;2;121-7

  • A functional polymorphism in the promoter region of the monoamine oxidase A gene is associated with the cigarette smoking quantity in alcohol-dependent heavy smokers.

    Wiesbeck GA, Wodarz N, Weijers HG, Dursteler-MacFarland KM, Wurst FM, Walter M and Boening J

    Division of Substance Use Disorders, Psychiatric University Hospital Basel, Basel, Switzerland. gerhard.wiesbeck.upkbs.ch

    Tobacco smoking represents a leading cause of morbidity and mortality with a strong dose-response relation between the amount of smoking and the risks of tobacco-related diseases and death. The quantity that is smoked is determined predominantly by genetic factors. The present study examined whether there is an association between the quantity of cigarettes smoked and length variation of a functional 30-bp repeat polymorphism in the promoter region of the monoamine oxidase A (MAO-A) gene. The number of 30-bp repeats, which is associated with enzyme activity was assessed in 121 Caucasian men suffering from both alcohol and tobacco dependence. Analysis revealed that the highly active long allele (4 repeat) is associated with a significantly greater amount of cigarette smoking in comparison with the less active short allele (3 repeat). In a logistic regression model (dichotomized), smoking quantity was significantly predicted by MAO-A genotype while no other variable (age, height, body weight, frequency of smoking, quantity and frequency of alcohol consumption) met the significance level. Since tobacco smoke is a potent inhibitor of MAO-A, this result could be regarded as a genotype-related dosage effect. Taken together, in alcohol-dependent heavily smoking men there is evidence for a MAO-A gene-associated effect on the quantity that is smoked as reflected by the daily number of cigarettes consumed.

    Neuropsychobiology 2006;53;4;181-5

  • No allele variation of the MAOA gene promoter in male Chinese subjects with attention deficit hyperactivity disorder.

    Lung FW, Yang P, Cheng TS and Kao WT

    Department of Psychiatry, Military Kaohsiung General Hospital, Kaohsiung, Taiwan, ROC. forwey@seed.net.tw

    The aim of the current study was to examine any difference in the repeat sequence of the monoamine oxidase A (MAOA) gene promoter between males with attention deficit hyperactivity disorder (ADHD) and randomly selected subjects in a community. The role of the MAOA gene promoter in ADHD cases was also investigated. The total of 244 participants included 57 male ADHD subjects as the case group and 187 males, also in southern Taiwan, as the community controls. There was no significantly different distribution in the repeat sequence of the MAOA gene promoter (chi2 = 3.895, d.f. = 3, p = 0.273), and no significantly different distribution of 'long-form' and 'short-form' alleles between the ADHD group and the male community group was noted (chi2 = 2.484, d.f. = 1, p = 0.115). Some aspects of clinical response are mentioned in the discussion of this study which are worth exploring further in the future.

    Neuropsychobiology 2006;54;3;147-51

  • Temperament and character in mood disorders: influence of DRD4, SERTPR, TPH and MAO-A polymorphisms.

    Serretti A, Mandelli L, Lorenzi C, Landoni S, Calati R, Insacco C and Cloninger CR

    Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan, Italy. serretti.alessandro@hsr.it

    Gene variants exert a complex range of effects on human normal and abnormal behavior. We previously reported the effect of gene variants in serotoninergic and dopaminergic pathways, in a range of clinical features in mood disorders, such as symptomathology, periodicity, social adjustment and treatment response. In this paper we hypothesized that the same gene variants could influence temperamental traits in mood disorders patients. We focused on genes of the serotoninergic and dopaminergic systems (dopamine receptor D4 gene, DRD4; serotonin transporter gene, promoter region SERTPR; tryptophan hydroxylase gene, TPH; monoamine oxidase A gene, MAO-A). Two hundred and seven euthymic subjects, affected by major depressive disorder (n=73) and bipolar disorder (n=134) were assessed by the Cloninger's Temperament and Character Inventory (TCI) and typed using PCR-based analyses. Possible stratification factors such as demographic, clinical and other temperamental factors were also taken into account. We observed that homozygosity for the short SERTPR allele was associated with low novelty-seeking scores (p=0.006) and genotypes containing the DRD4 long allele were marginally associated with low harm avoidance (p=0.05). Finally, the long MAO-A allele was associated with decreased persistence scores among females (p=0.006). Our observation of a pattern of influence on temperamental dimension exerted by serotonergic and dopaminergic genes suggests that the contribution of these polymorphisms to the clinical presentation of mood disorders could be mediated by an influence on personality differences.

    Neuropsychobiology 2006;53;1;9-16

  • No association between monoamine oxidase A promoter polymorphism and personality traits in Japanese females.

    Hakamata Y, Takahashi N, Ishihara R, Saito S, Ozaki N, Honjo S, Ono Y and Inada T

    Department of Psychology and Human Developmental Sciences, Nagoya University, Graduate School of Education and Human Development, Japan.

    Monoamine oxidase A (MAO-A) is an enzyme involved in the metabolism of monoamine neurotransmitters such as dopamine, serotonin, and noradrenaline in the brain. Previous studies have demonstrated a significant association between MAO-A gene polymorphism and personality traits in males. The purpose of the present study was to examine this association in females. The subjects were 219 healthy Japanese females. We genotyped a variable number of tandem repeats located upstream of the MAO-A gene. Personality traits were assessed using the Temperament and Character Inventory (TCI). There was no association between any personality trait and MAO-A genotype. The present results do not support the hypothesis that MAO-A gene polymorphism is related to certain personality traits in females.

    Neuroscience letters 2005;389;3;121-3

  • CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents.

    Huang S, Cook DG, Hinks LJ, Chen XH, Ye S, Gilg JA, Jarvis MJ, Whincup PH and Day IN

    Human Genetics Division, Duthie Building, Southampton General Hospital, UK.

    Objectives: Smoking is a major cause of death and often initiates in adolescence. Mutations in CYP2A6 slow metabolism of nicotine to cotinine. Haploinsufficiency in adults is associated with lower cigarette consumption, lower cotinine level and higher quit rates. Other genes are also implicated in smoking behaviour. We explored smoking behaviour and cotinine levels in relation to genotypes in adolescents.

    Methods: 1518 subjects from the Ten Towns Heart Health Study were genotyped for CYP2A6 alleles *1A, *1B, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBH(rs77905), MAOA(rs1801291+VNTR), DRD4(VNTR) and 5HT2A(rs6313) were also studied. Smoking status was established by questionnaire and salivary cotinine measurement at 13-15 and 18 years.

    Results: No significant associations were identified for DBH, MAOA, DRD4 and 5HT2A markers, with smoking status or cotinine level at either age. At age 18, haploinsufficiency (HI) for CYP2A6 was associated with a higher odds of being a current smoker compared with the *1B carriers (WT1B) (OR = 2.23 (1.16, 4.27) for current versus ex); *1A homozygotes (WT1A) were also at slightly higher risk (OR = 1.44 (1.01, 2.06)). Partial haploinsufficiency (PHI) was not associated with being a current smoker. There were no significant associations at age 13-15. PHI and HI were associated with higher cotinine levels amongst smokers at both 13-15 and at 18 years compared with WT1B and WT1A groups.

    Conclusions: CYP2A6 haploinsufficiency increases likelihood of continuing smoking in teenagers. We hypothesize an explanatory 'occupancy' model to explain why haploinsufficiency results in faster progression to nicotine dependence, but lower subsequent consumption.

    Pharmacogenetics and genomics 2005;15;12;839-50

  • MAOA haplotypes associated with thrombocyte-MAO activity.

    Jansson M, McCarthy S, Sullivan PF, Dickman P, Andersson B, Oreland L, Schalling M and Pedersen NL

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. marten.jansson@cmm.ki.se

    Background: The aim was to ascertain whether thrombocyte MAO (trbc-MAO) activity and depressed state are genetically associated with the MAO locus on chromosome X (Xp11.3 - 11.4). We performed novel sequencing of the MAO locus and validated genetic variants found in public databases prior to constructing haplotypes of the MAO locus in a Swedish sample (N = 573 individuals).

    Results: Our results reveal a profound SNP desert in the MAOB gene. Both the MAOA and MAOB genes segregate as two distinct LD blocks. We found a significant association between two MAOA gene haplotypes and reduced trbc-MAO activity, but no association with depressed state.

    Conclusion: The MAO locus seems to have an effect on trbc-MAO activity in the study population. The findings suggest incomplete X-chromosome inactivation at this locus. It is plausible that a gene-dosage effect can provide some insight into the greater prevalence of depressed state in females than males.

    Funded by: NIA NIH HHS: AG 04563, AG 10175, R01 AG010175

    BMC genetics 2005;6;46

  • Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B.

    De Colibus L, Li M, Binda C, Lustig A, Edmondson DE and Mattevi A

    Department of Genetics and Microbiology, University of Pavia, via Abbiategrasso 207, 27100 Pavia, Italy.

    The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO B), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic behavior of a monomeric form rather than the dimeric form of hMAO B and rat MAO A. hMAO A's active site consists of a single hydrophobic cavity of approximately 550 A3, which is smaller than that determined from the structure of deprenyl-inhibited hMAO B (approximately 700 A3) but larger than that of rat MAO A (approximately 450 A3). An important component of the active site structure of hMAO A is the loop conformation of residues 210-216, which differs from that of hMAO B and rat MAO A. The origin of this structural alteration is suggested to result from long-range interactions in the monomeric form of the enzyme. In addition to serving as a basis for the development of hMAO A specific inhibitors, these data support the proposal that hMAO A involves a change from the dimeric to the monomeric form through a Glu-151 --> Lys mutation that is specific of hMAO A [Andrès, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum. Genet. 115, 377-386]. These considerations put into question the use of MAO A from nonhuman sources in drug development for use in humans.

    Funded by: NIGMS NIH HHS: GM-29433, R01 GM029433

    Proceedings of the National Academy of Sciences of the United States of America 2005;102;36;12684-9

  • The monoamine oxidase A gene may influence the means used in suicide attempts.

    Courtet P, Jollant F, Buresi C, Castelnau D, Mouthon D and Malafosse A

    Department of Psychological Medicine and Psychiatry, Lapeyronie Hospital, Montpellier Cedex, France. p-courtet@chu-montpellier.fr

    Objective: Compelling evidence suggests that serotonin system dysfunction is associated with certain behavioral disorders, including suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the monoamine oxidase A gene (uVNTR) was recently identified and the presence of the 2-3 alleles was found to be associated with a higher level of transcription, central nervous system serotonergic responsivity and impulsive aggression. A dinucleotide repeat in intron 2 of the gene (monoamine oxidase A-CAn) has been described previously, and is in linkage disequilibrium with the variable number of tandom repeats (VNTR). The aim of the study was to investigate, in a large sample, whether the monoamine oxidase A gene was involved in the susceptibility to suicidal behavior.

    Methods: We genotyped 738 West European Caucasians, who had made suicide attempts, and 222 controls of the same ethnic origin, with no history of suicidal behavior. The two variants of the monoamine oxidase A gene have been tested.

    Results: We did not find any association between the two monoamine oxidase A gene variants and suicidal behavior. However, the frequency of the uVNTR 2-3 alleles was significantly higher in men who had attempted suicide by violent means than in men who had used non-violent means. The odds ratio for the uVNTR 2-3 alleles versus the uVNTR 1-4 alleles was 2.17 [95% confidence interval (1.08-4.35)]. Haplotypes did not allow strengthening the effect observed with the uVNTR.

    Conclusion: These results suggest that an excess of high-activity monoamine oxidase A gene promoter alleles may be associated with traits orienting suicidal behavior towards a violent act.

    Psychiatric genetics 2005;15;3;189-93

  • Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response.

    Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC and Yang CW

    Yu's Psychiatric Clinic, Kaohsiung, Taiwan, ROC.

    Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of biogenic amines, may be implicated in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied a variable-number-tandem-repeat (VNTR) polymorphism in the promoter region of the MAOA gene in a Chinese population of 230 MDD patients and 217 controls. We also examined the association of this polymorphism and antidepressant therapeutic response in the MDD patients who underwent a 4-week fluoxetine treatment. Our results showed a significantly increased frequency of 4-repeat (4R) allele in MDD patients, especially in the female population. Furthermore, MDD female patients who were 3R homozygotes had a significantly better response to 4-week fluoxetine treatment when compared to 4R carriers (p=0.024), but there was a nonsignificant difference found in male patients (p=0.081). Since the 4R allele transcribed 2-10 times more efficiently than those with 3R allele, our findings suggest that the MAOA-uVNTR may be involved in the pathogenesis of MDD and the antidepressant therapeutic mechanisms in Chinese population, and that there may be a gender effect in this association.

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2005;30;9;1719-23

  • Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity.

    Jacob CP, Müller J, Schmidt M, Hohenberger K, Gutknecht L, Reif A, Schmidtke A, Mössner R and Lesch KP

    Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany. psychpol@mail.uni-wuerzburg.de

    Genetic variants of the monoamine oxidase A (MAOA) have been associated with aggression-, anxiety-, and addiction-related behavior in several nonclinical and clinical populations. Here, we investigated the influence of allelic variation of MAOA activity on aggression-related personality traits and disease risk in patients with personality disorders. Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, and C. Personality features were assessed by the revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. The genotype of the MAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients with personality disorders and in 281 healthy controls. MAOA genotype was significantly associated with cluster B personality disorders (chi2=7.77, p=0.005, df=1) but not with cluster C personality disorders. In total, 26.0% of cluster B patients were hemi- or homozygous for the low-activity variant of the MAOA genotype, compared to 16.4% in the control group. Associations between MAOA variants and personality domains related to impulsivity and aggressiveness were inconsistent. Our findings further support the notion that allelic variation of MAOA activity contributes modestly to the balance of hyper- (impulsive-aggressive) and hyporeactive (anxious-depressive) traits.

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2005;30;9;1711-8

  • Gene-gene interaction between MAOA and COMT in suicidal behavior.

    De Luca V, Tharmalingam S, Sicard T and Kennedy JL

    Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Ont., Canada. Vincenzo_Deluca@camh.net

    Several lines of evidence suggest that suicidal behavior is associated with altered noradrenergic neurotransmission. Noradrenaline (NA) is catabolized by monoamine oxidase A (MAOA) and cathecol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk for attempted suicide. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the Val 108/158 Met COMT polymorphism in 305 families with at least one member having bipolar disorder (BD). No association with history of suicide attempt was found either in the MAOA polymorphisms (VNTR:LRS = 1.90, d.f. = 1, p = 0.16; 941T > G:LRS = 1.39, d.f. = 1, p = 0.23), or with the Val 158 Met polymorphism (LRS = 1.61, d.f.=1, p = 0.20). When we performed the haplotype analysis for MAOA gene, we found no association between suicide attempt and haplotype distribution (LRS = 3.07, d.f. = 2, p = 0.21). As both genes are involved in degrading noradreanline, we also tested the hypothesis of epistasis between MAOA polymorphisms and Val158Met, however, no additive effect was found in conferring risk for suicide attempt. These findings suggest that MAOA and COMT genes may not influence suicidal behavior in patients with bipolar disorder.

    Neuroscience letters 2005;383;1-2;151-4

  • Association of MAO A polymorphism and alcoholism in Brazilian females.

    Guindalini C, Scivoletto S, Ferreira RG, Nishimura A, Zilberman ML, Peluso MM and Zatz M

    Department of Biology, Human Genome Research Center, Institute of Biosciences, University of São Paulo, Rua do Matão-Travessa 13, No. 106, Cidade Universitária CEP, 05508-090 São Paulo, Brazil.

    Among the different possible genes involved in the alcoholism etiology, the X-linked monoamine oxidase A gene is a good candidate. The aim of this study was to assess whether a functional VNTR polymorphism in the promoter region of the monoamine oxidase A gene is associated with alcoholism, comparing patients of both sexes. Ninety-three alcohol-dependent patients (51 males, 42 females) and 93 sex-matched normal controls were engaged. In the total sample, the genotype containing at least one three-repeat allele was significantly more frequent among alcohol-dependent patients than controls (P=0.01). However, when the two sexes were analyzed separately, the difference was statistically significant only for females. This is of particular interest as rates of alcoholism in Brazil are markedly lower in females. Our results suggest that this monoamine oxidase A polymorphism could play a role in susceptibility to alcoholism, which may differ across sexes.

    Psychiatric genetics 2005;15;2;141-4

  • Associations between serotonin-related gene polymorphisms and panic disorder.

    Maron E, Lang A, Tasa G, Liivlaid L, Tõru I, Must A, Vasar V and Shlik J

    Department of Psychiatry, University of Tartu, Raja, Estonia. Edurad.Maron@klinikum.ee

    Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD.

    The international journal of neuropsychopharmacology 2005;8;2;261-6

  • Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment.

    Haberstick BC, Lessem JM, Hopfer CJ, Smolen A, Ehringer MA, Timberlake D and Hewitt JK

    Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309-0447, USA. habersti@ibg.colorado.edu

    There is a robust relationship between the experience of maltreatment in childhood and later antisocial behaviors amongst adolescents and adults. Animal and human studies suggest that variation in monoamine oxidase A (MAOA) genotype may moderate the effects of maltreatment. Self-reported conduct problems and criminal convictions amongst sibling-pairs from the National Longitudinal Study of Adolescent Health were tested for association with reports of maltreatment before and after the age of 12. MAOA promoter polymorphisms were tested for possible moderation effects. Maltreatment predicted conduct problems and criminal convictions. MAOA genotype did not have a significant moderating effect in any of the six analyses that were conducted. We did not replicate a previous report that MAOA polymorphisms moderated the relationship between maltreatment and conduct problems. There was, however, a non-significant trend in the predicted direction. Additional studies will be needed before firm conclusions can be drawn about this hypothesized genotype-environment interaction.

    Funded by: NICHD NIH HHS: HD07289, P01-HD31921; NIDA NIH HHS: R01 DA15522-01

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;135B;1;59-64

  • Epistatic interaction between the monoamine oxidase A and serotonin transporter genes in anorexia nervosa.

    Urwin RE and Nunn KP

    Department of Psychological Medicine, The Children's Hospital at Westmead, Westmead, NSW, Australia. RuthU@chw.edu.au

    The serotonin (5-HT) and norepinephrine (NE) systems are likely involved in the aetiology of anorexia nervosa (AN) as sufferers are premorbidly anxious. Specifically, we hypothesize that genes encoding proteins, which clear 5-HT and NE from the synapse, are prime candidates for affecting susceptibility to AN. Supporting our hypothesis, we earlier showed that the NE transporter (NET) and monoamine oxidase A (MAOA) genes appear to contribute additively to increased risk of developing restricting AN (AN-R). With regard to the MAOA gene, a sequence variant that increases MAOA activity and has suggested association with the anxiety condition, panic disorder was preferentially transmitted from parents to affected children. Here we provide evidence in support of interaction between the MAOA and serotonin transporter (SERT) genes in 114 AN nuclear families (patient with AN plus biological parents). A SERT gene genotype with no apparent individual effect on risk and known to be associated with anxiety is preferentially transmitted to children with AN (chi2 trend=9.457, 1 df, P=0.0021) and AN-R alone (chi2 trend=7.477, 1 df, P=0.0063) when the 'more active' MAOA gene variant is also transmitted. The increased risk of developing the disorder is up to eight times greater than the risk imposed by the MAOA gene variant alone--an example of synergistic epistatic interaction. If independently replicated, our findings to date suggest that we may have identified three genes affecting susceptibility to AN, particularly AN-R: the MAOA, SERT, and NET genes.

    European journal of human genetics : EJHG 2005;13;3;370-5

  • Telomeric length varies with age and polymorphisms of the MAOA gene promoter in peripheral blood cells obtained from a community in Taiwan.

    Lung FW, Fan PL, Chen NC and Shu BC

    Department of Psychiatry, Military Kaohsiung General Hospital, No. 2 Chung Cheng 1st Rd, Kaohsiung, Taiwan. forwey@ksts.seed.net.tw

    Objective: Telomere shortening and increased MAOA gene activity both occur with aging. We undertook to develop a predictive model of telomere shortening and to investigate the possible association between MAOA gene promoter polymorphisms and telomere length as influenced by age and gender.

    Methods: A stratified random household sample was selected from a community in southern Taiwan. Of 1231 subjects attending our health-screening program, 441 agreed to have additional venous blood withdrawn for DNA extraction and genetic study. Exactly 433 subjects completed the questionnaires and genetic analysis. Their telomere lengths were distributed (6.4-11.63 kb).

    Results: The rate of shortening per year was 69 base pairs, and the gender difference in length was not statistically significant (F = 0.091, P = 0.763). The lognormal distribution of telomere lengths was linear. The polynomial regression analysis showed Ln (telomere length) = -2.57-0.007 x age - 0.34 MAOA (adjusted R-square = 0.60). The gender effect on telomere length was not statistically significant (P = 0.52). No interaction effects were found between age, gender and MAOA gene polymorphisms. The high-activity allele of the MAOA promoter polymorphisms were negatively associated with telomere length (P = 0.013). Structural equation modeling confirmed the null model structure. The present data suggest that high-activity MAOA promoter gene polymorphisms, as in aging, are a risk factor for telomeric shortening.

    Conclusions: Central nervous system serotonergic activity correlates with human aggressive behavior and depression in many studies, and the MAOA promoter gene may also serve as a clinical marker in the treatment of cardiovascular disease. The predictive model and table of telomere length presented in this study will provide a quick reference for future studies.

    Psychiatric genetics 2005;15;1;31-5

  • Monoamine oxidases A and B gene polymorphisms in migraine patients.

    Filic V, Vladic A, Stefulj J, Cicin-Sain L, Balija M, Sucic Z and Jernej B

    Laboratory of Neurochemistry and Molecular Neurobiology, Dept. of Molecular Biology, Rudjer Boskovic Institute, Bijenicka 54, Zagreb HR-10000, Croatia.

    Abnormal cortical activity and brainstem functioning are considered the possible etiopathogenetic factors of migraine. Monoamine oxidase A and B (MAO-A and -B) regulate the levels of monoamine neurotransmitters, so changes in their activity could participate in migraine pathogenesis. We have investigated the possible association of MAO-A and -B alleles and haplotypes with two common types of migraine, i.e. migraine without aura (MO) and migraine with aura (MA), on the sample of 110 migraineours (80 MO and 30 MA) and 150 controls. MAO-A promoter and MAO-B intron 13 polymorphisms were genotyped by the PCR-based methods. In addition, we have reevaluated the reported association between MAO-B intron 13 polymorphism and platelet MAO-B activity. The platelet MAO-B activity was determined fluorimetrically using kynuramine as a substrate. We have found a tendency toward association of the shorter variant of MAO-A gene promoter with migraine without aura in male subjects. Regarding investigated MAO-B polymorphism, no association with migraine or with platelet MAO-B activity was found. The suggestive association of the variant in MAO-A gene with migraine is considered worthy of independent replication. On the other hand, further studies on MAO-B polymorphism in migraine do not seem promising.

    Journal of the neurological sciences 2005;228;2;149-53

  • A stable tyrosyl radical in monoamine oxidase A.

    Rigby SE, Hynson RM, Ramsay RR, Munro AW and Scrutton NS

    Department of Biological Sciences, Queen Mary College, University of London, London E1 4NS, United Kingdom.

    We present spectroscopic evidence consistent with the presence of a stable tyrosyl radical in partially reduced human monoamine oxidase (MAO) A. The radical forms following single electron donation to MAO A and exists in equilibrium with the FAD flavosemiquinone. Oxidative formation of the tyrosyl radical in MAO is not reliant on neighboring metal centers and uniquely requires reduction of the active site flavin to facilitate oxidation of a tyrosyl side chain. The identified tyrosyl radical provides the key missing link in support of the single electron transfer mechanism for amine oxidation by MAO enzymes.

    The Journal of biological chemistry 2005;280;6;4627-31

  • Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking risk in young women.

    Herman AI, Kaiss KM, Ma R, Philbeck JW, Hasan A, Dasti H and DePetrillo PB

    Unit of Clinical and Biochemical Pharmacology, Laboratory of Clinical Studies, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.

    The short allelic variant of the serotonin transporter protein promoter polymorphism (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;133B;1;74-8

  • Relationship of MAO-A promoter (u-VNTR) and COMT (V158M) gene polymorphisms to CSF monoamine metabolites levels in a psychiatric sample of caucasians: A preliminary report.

    Zalsman G, Huang YY, Harkavy-Friedman JM, Oquendo MA, Ellis SP and Mann JJ

    Department of Neuroscience, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive, Box 42, New York, NY 10032, USA. zalsman@neuron.cpmc.columbia.edu

    Monoamine oxidase A gene promoter (MAOA-uVNTR) and catechol-O-methyltransferase V158M (COMT-V158M) gene functional polymorphisms are reported to be associated with impulsive-aggression, but a biological intermediate effect remains to be determined. This study assessed the association of these polymorphisms with cerebrospinal fluid (CSF) monoamine metabolites as endophenotypes. Ninety-eight Caucasian psychiatric subjects were assessed for Axis I and II diagnosis. Subjects were genotyped for the functional polymorphisms, MAOA-uVNTR and COMT-V158M. CSF was obtained by lumbar puncture. Relationships of the two polymorphism to monoamine metabolites: HVA, 5-HIAA, and MHPG were examined. The higher-expressing MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males only (n = 46) (195.80 pmol/ml, SD = 61.64 vs. 161.13, SD = 50.23, respectively; P = 0.042). No association was found with diagnosis. COMT-V158M had no association with CSF monoamine metabolites. The association of MAOA-uVNTR with dopaminergic activity in males is a preliminary finding that needs to be replicated in a larger sample of Caucasian males and relationships sought with clinical phenotypes. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

    Funded by: NIMH NIH HHS: MH48514, MH62185

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;132B;1;100-3

  • Association study of a functional MAOA-uVNTR gene polymorphism and cognitive function in healthy females.

    Yu YW, Tsai SJ, Hong CJ, Chen MC, Yang CW and Chen TJ

    Yu' s Psychiatric Clinic, Taiwan, ROC.

    Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the degradation of dopamine, serotonin and norepinephrine and these neurotransmitters are hypothesized to be involved in the cognitive function of humans. This study of a cohort of 191 healthy young Chinese females attempts to utilize the intelligence quotient (IQ), Wisconsin Card Sorting Test (WCST) and P300 event-related potentials as cognitive assessments for testing the relationship between the polymorphism with a variable number of tandem repeats (VNTR) in the upstream regulatory region (MAOA-uVNTR) and cognition. The results demonstrate that subjects bearing the 4/4-repeat genotype have a significantly higher full IQ than subjects bearing the 3/3-repeat genotype. However, there is no significant association between this MAOA-uVNTR polymorphism and the WCST and P300. Our study shows that the MAOA-uVNTR genetic polymorphism plays a role in the IQ; however, this may be a chance finding as the result was negative after using the Bonferroni adjustment. Therefore, we suggest that our study should be replicated and that the testing method, sex, disease and ethnicity should also be considered in future studies.

    Neuropsychobiology 2005;52;2;77-82

  • Association study of a functional MAOA-uVNTR gene polymorphism and personality traits in Chinese young females.

    Yu YW, Yang CW, Wu HC, Tsai SJ, Hong CJ, Chen MC and Chen TJ

    Yu's Psychiatric Clinic, Kaohsiung, Taiwan.

    Monoamine oxidase A (MAOA), a mitochondrial outer membrane enzyme, degrades biogenic amines including norepinephrine, dopamine and serotonin, which have been implicated in the expression of personality traits. We tested the associations between functional MAOA-uVNTR genetic variants and personality traits in a cohort of 370 healthy young Chinese females. Subjects who were homozygous for the 4-repeat allele of the MAOA-uVNTR gene tended to have a higher total score on the Harm Avoidance (HA) dimension of the Tridimensional Personality Questionnaire (TPQ) (p = 0.056), and had a significantly higher score on subdimension 4 of HA (p = 0.020) compared with the 3-repeat carriers. No significant association was demonstrated for MAOA-uVNTR polymorphism and the other two dimensions (Novelty Seeking and Reward Dependence) of TPQ. These results suggest that genetic variants of the MAOA gene may play a role in HA, but not in Novelty Seeking or Reward Dependence.

    Neuropsychobiology 2005;52;3;118-21

  • Monoamine oxidase a polymorphism in Brazilian patients: risk factor for late-onset Alzheimer's disease?

    Nishimura AL, Guindalini C, Oliveira JR, Nitrini R, Bahia VS, de Brito-Marques PR, Otto PA and Zatz M

    Human Genome Research Center, Biology Department, Institute of Biosciences, São Paulo University (IBUSP), São Paulo, Brazil.

    Different studies have attempted to find polymorphisms involved in the serotonergic pathway that could be involved in mood disorders and late-onset Alzheimer's disease (LOAD) symptoms. Here, we compared the frequency of two polymorphisms: monoamine oxidase A (MAOA) and serotonin transporter in LOAD patients versus controls. No evidence of association was observed when these polymorphisms were compared separately; however, the combination of the MAOA allele 1+the short allele of 5-HTTLPR+ApoE-epsilon4 was significantly more frequent in patients than in controls. It reinforces the hypothesis that different genes acting together might play a role in AD susceptibility. Based on these data, we suggest replicating these studies in larger samples of LOAD patients belonging to different ethnic groups.

    Journal of molecular neuroscience : MN 2005;27;2;213-7

  • Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders.

    Gutiérrez B, Arias B, Gastó C, Catalán R, Papiol S, Pintor L and Fañanás L

    Unitat d'Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.

    Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity. In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression.

    Psychiatric genetics 2004;14;4;203-8

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Gene-environment interaction analysis of serotonin system markers with adolescent depression.

    Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P, Plomin R and Craig IW

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK. t.eley@iop.kcl.ac.uk

    We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.

    Molecular psychiatry 2004;9;10;908-15

  • Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage.

    Andrés AM, Soldevila M, Navarro A, Kidd KK, Oliva B and Bertranpetit J

    Unitat de Biologia Evolutiva, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

    Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as K(a)/ K(s) would not have detected the selective history of the gene.

    Human genetics 2004;115;5;377-86

  • MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males.

    Du L, Bakish D, Ravindran A and Hrdina PD

    Institute of Mental Health Research, University of Ottawa, 1145 Carling Ave, Ontario K1Z 7K4, Canada.

    We investigated whether the genetic variants of the MAO-A gene were associated with major depression and/or the clusters of depressive symptoms. The EcoRV and the uVNTR polymorphisms were studied in a population of 191 patients with major depression and 233 control subjects. The EcoRV polymorphism was found to be associated with depression in males but not in females. Haplotype analysis revealed that one of the haplotypes (EcoRV2-uVNTR1) was significantly more frequent among male patients than male controls. Among the HAMD symptom clusters, insomnia scores were significantly higher in male patients carrying allele 2 of the EcoRV polymorphism. These data suggest that the EcoRV and uVNTR polymorphisms may be involved in the pathogenesis of major depression and associated with insomnia in depressed patients.

    Neuroreport 2004;15;13;2097-101

  • [Association between the functional monoamine oxidase A gene polymorphism and aggressively driving behavior].

    Li FZ, Li CJ, Long YF, Zhan CL, Yao W, Tang HF and Jin H

    Department of Occupational Health, School of Public Health, Sichuan University, Chengdu 610041, China.

    Objective: This study is purposed to explore the relationship between aggressively driving behavior and functional polymorphism in the promoter region of the monoamine oxidase-A (MAOA) gene.

    Methods: A total of 348 automobile drivers were investigated with Deffenbacher's driver anger scale, driving vengeance questionnaire (DVQ) and driver aggression behavior questionnaire. Eighty-eight drivers were selected as more, medium and less aggressive group, each. Polymerase chain reaction (PCR) and 2.5% agarose gel electrophoresisi were adopted to detect the polymorphism of functional 30 bp-uVNTR in the promoter region of the X-chromosomal MAOA gene and their frequencies of varied genotypes were estimated.

    Results: Two alleles with 3 and 4 repeats of 30 bp-uVNTR were detected in the drivers. Among the more aggressive group, number of the allele with 3 repeats of 30 bp-uVNTR (63/88) was significantly more than that with 4 repeats (25/88) (chi(2) = 10.21, P < 0.01), and number of the allele with 4 repeats of 30 bp-uVNTR was more in the less aggressive group, indicating that persons with allele of 3 repeats of 30 bp VNTR were more aggressive in their driving than those with 4 repeats.

    Conclusions: Aggressively driving behavior in drivers possibly related to their functional MAOA-uVNTR polymorphism. Effect of the gene on aggressively driving behavior should be further studied.

    Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 2004;38;5;321-3

  • Investigation of serotonin-related genes in antidepressant response.

    Peters EJ, Slager SL, McGrath PJ, Knowles JA and Hamilton SP

    Department of Psychiatry, University of California, San Francisco, CA 94143-0984, USA.

    In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.

    Funded by: NCI NIH HHS: CA 94919; NIMH NIH HHS: R10 MH56058

    Molecular psychiatry 2004;9;9;879-89

  • Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum.

    Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepień G, Grzywacz A and Kucharska-Mazur J

    Pomeranian Medical University, Department of Psychiatry, Broniewskiego 26, 71-460 Szczecin, Poland. samoj@sci.pam.szczecin.pl

    Recent studies provide evidence that anxiety disorders may be linked to malfunction of serotonin neurotransmission or impaired activity of enzymes metabolising the catecholamines. Functional polymorphisms in the MAO-A uVNTR promoter gene, the COMT gene (Val158Met) exon 4, and the 5-HTT promoter gene (44 bp ins/del) were investigated in 101 patients with phobic disorders of the anxiety spectrum and 202 controls matched to the patients for sex, age and ethnicity. There were no significant differences between controls and patients in the allele and genotype frequencies of the 5-HTT and COMT gene polymorphisms. The frequency of >3 repeat alleles of the MAO-A gene polymorphism was significantly higher in female patients suffering from anxiety disorders, specifically panic attacks and generalized anxiety disorder. There was also a trend for the more frequent presence of >3 repeat alleles in female patients with agoraphobia and specific phobia, in contrast to female patients with social phobia, who did not differ from controls. The results support a possible role of the MAO-A gene in anxiety disorders.

    Psychiatry research 2004;128;1;21-6

  • An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences.

    Huang YY, Cate SP, Battistuzzi C, Oquendo MA, Brent D and Mann JJ

    Department of Neuroscience, New York State Psychiatric Institute, Department of Psychiatry, Columbia University College of Physicians & Surgeons, New York, NY, USA.

    Monoamine oxidase A (MAOA) activity is altered in mood disorders and lower activity associated with aggressive behavior. The gene has a functional polymorphism with a variable number tandem repeat (VNTR) in the upstream regulatory region (MAOA-uVNTR). In this study, we examined possible associations between the MAOA-uVNTR polymorphism and mood disorders, suicidal behavior, aggression/impulsivity, and effects of reported childhood abuse. In total, 663 unrelated subjects with a psychiatric disorder and 104 healthy volunteers were genotyped for the 30 base pair functional VNTR. A novel repeat variation was identified. No statistically significant associations were found between this functional MAOA-uVNTR polymorphism and mood disorders or suicide attempts. However, the lower expression allele was associated with a history of abuse before 15 years of age in male subjects and with higher impulsivity in males but not females. Our results suggest that the lower expression of the MAOA-uVNTR polymorphism is related to a history of early abuse and may sensitize males, but not females, to the effects of early abuse experiences on impulsive traits in adulthood. The polymorphism may be a marker for impulsivity that in turn may contribute to the risk for abuse. This trait could then be further aggravated by abuse.

    Funded by: NIMH NIH HHS: MH48514, MH62185

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2004;29;8;1498-505

  • Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia.

    Zammit S, Jones G, Jones SJ, Norton N, Sanders RD, Milham C, McCarthy GM, Jones LA, Cardno AG, Gray M, Murphy KC, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, United Kingdom. zammits@cardiff.ac.uk

    Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;128B;1;19-20

  • Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers.

    Maron E, Tasa G, Tõru I, Lang A, Vasar V and Shlik J

    Department of Psychiatry, University of Tartu, Raja 31, Tartu 50417, Estonia. Eduard.Maron@kliinikum.ee

    Genetic regulation of the function of serotonin (5-HT) may be important for the neurobiology of panic disorder. In order to evaluate the influence of 5-HT-related gene variants on the vulnerability to panic attacks, we genotyped 32 healthy volunteers who participated in the study of the effect of 5-hydroxytryptophan on panic attacks induced with cholecystokinin tetrapeptide (CCK-4). The polymorphisms of interest included those of 5-HT transporter (5-HTTLPR) and monoamine oxidase A (MAO-A promoter region) genes. The results showed significant associations between certain genotypes and panic rate in females but not in male volunteers. Specifically, there was a significantly lower rate of CCK-4-induced panic attacks in female subjects who had MAO-A longer alleles or 5-HTTLPR short allele gene variants. These data suggest that functional genetic polymorphisms of the 5-HT system may influence the vulnerability to panic attacks and add to the growing evidence of inhibitory function of 5-HT in the neuronal circuitry of panic.

    The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 2004;5;3;149-54

  • Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia.

    Matsumoto C, Shinkai T, Hori H, Ohmori O and Nakamura J

    Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan. chima-sgy@umin.ac.jp

    Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD.

    Psychiatry research 2004;127;1-2;1-7

  • MAOA and persistent, pervasive childhood aggression.

    Beitchman JH, Mik HM, Ehtesham S, Douglas L and Kennedy JL

    Molecular psychiatry 2004;9;6;546-7

  • [Polymorphism of the serotonin system genes in some Finno-Ugric populations].

    Andreenkov OV, Osipova LP, Kulikov AV and Popova NK

    Polymorphic sites in the genes encoding monoamine oxidase A (MAO-A), serotonin transporter (hSERT) and 5-HT2A receptor were typed in Khant and Komi ethnic groups with the purpose of revealing possible interpopulation differences in genotype and allele frequencies. No statistically significant differences in the hSERT and 5-HT2A gene frequencies were detected. At the same time, the populations examined had statistically significantly different MAO-A genotype and allele frequencies. These results obtained indicate the prevalence of the site gain alleles of the EcoRV and Fnu4HI RFLP loci at the MAO-A gene in Komis and the of the corresponding site loss alleles in Khants.

    Genetika 2004;40;6;841-5

  • Analysis of monoamine oxidase A (MAO-A) promoter polymorphism in male heroin-dependent subjects: behavioural and personality correlates.

    Gerra G, Garofano L, Bosari S, Pellegrini C, Zaimovic A, Moi G, Bussandri M, Moi A, Brambilla F, Mameli A, Pizzamiglio M and Donnini C

    Centro Studi Farmaco-tossicodipendenze, Ser T, AUSL, Italy. g.gerra@palazzochigi.it

    The promoter of the monoamine oxidase A (MAO-A) gene was analysed to test whether length variation of the repeat polymorphism contributes to variation in individual vulnerability to aggressive-criminal behaviour, and liability to heroin dependence. The repeat number of the MAO-A polymorphism was assessed in 199 male subjects of Italian descent, a sample comprising 95 healthy subjects and 104 heroin-dependent subjects including 52 addicted individuals with violent behaviour and antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly higher in violent offenders among heroin addicts, compared to addicted individuals without antisocial behaviour (34.6 vs. 15.4%; p<0.03) and controls (18.9%; p<0.05). No significant difference was evidenced in the frequencies of the MAO-A alleles between heroin-dependent subjects in general and control subjects. High activity 4-repeat allele frequency was significantly higher in addicted individuals without antisocial behavior compared to antisocial-aggressive heroin-dependent subjects (76.9 vs. 55.8%; p<0.02). Buss Durkee Hostility Inventory (BDHI) mean total scores were significantly higher in heroin addicts than in controls (p<0.001), and in antisocial-violent heroin addicts in comparison with addicted individuals without antisocial behaviour (p<0.005). Among heroin addicts BDHI irritability, suspiciousness and resentment subscales scores were found significantly higher in low activity 3-repeat allele subjects than in high activity alleles subjects (p<0.001; p<0.05; p<0.05, respectively). No association was found between MAO-A polymorphism and suicide history. Our findings suggest that the low-activity 3-repeat allele of the MAO-A promoter polymorphism confers increased susceptibility to antisocial-violent behavior and aggressiveness, rather than drug dependence per se, in heroin-dependent males.

    Journal of neural transmission (Vienna, Austria : 1996) 2004;111;5;611-21

  • Association analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine.

    Marziniak M, Mössner R, Benninghoff J, Syagailo YV, Lesch KP and Sommer C

    Department of Neurology, University of Würzburg, Würzburg, Germany. dr.martin.marziniak@uniklinik-saarland.de

    Migraine affects about 15% of the adult population. Serotonergic and dopaminergic systems are believed to be involved in its pathophysiology. One of the key enzymes in the degradation of serotonin and to a lesser extent of dopamine is monoamine oxidase A (MAO-A). In this study we investigated a functionally relevant gene-linked polymorphic repetitive sequence (LPR) located approximately 1.2 kb upstream of the ATG codon in the MAO-A-promotor gene. 119 patients with migraine and 229 controls were tested. The allelic distribution of the controls and the migraine patients did not show significant differences with respect to the low- and high-activity alleles. Moreover, effectiveness of the potent serotonergic antimigraine agents, triptans, which are metabolized by MAO-A, was clinically not affected by the MAO-A-LPR in our patients. These findings thus indicate that there is no association between the functional MAO-A-LPR and susceptibility to migraine.

    Journal of neural transmission (Vienna, Austria : 1996) 2004;111;5;603-9

  • Association of variations in monoamine oxidases A and B with Parkinson's disease subgroups.

    Parsian A, Racette B, Zhang ZH, Rundle M and Perlmutter JS

    Department of Molecular and Cellular Biology, University of Louisville Health Sciences Center, 501 S Preston Street, Rm 301, Louisville, KY 40292, USA. parsian@louisville.edu

    Idiopathic Parkinson's disease (PD) is an age dependent, neurodegenerative disorder and is predominantly a sporadic disease. A minority of patients has a positive family history for PD and the majority of those families exhibit a complex mode of inheritance. The monoamine oxidases A and B (MAO-A and -B) genes, which are involved in serotonin and dopamine metabolism, are possible candidate genes for susceptibility to PD. Previous association studies of MAO-A and -B in PD have been inconclusive. To determine the role of MAO-A and -B in the development of PD, we screened a sample of 96 patients with familial PD, 164 with sporadic PD, and 180 matched normal controls with dinucleotide repeat markers in these genes. MAO-A and -B gene polymorphisms were strongly associated with total PD (p < 0.00001), familial PD (p < 0.00001), and sporadic PD (p < 0.00001). There were no significant differences between familial or sporadic PD with age of onset younger than 50 years compared to those with age of onset older than 51 years for both MAO-A and -B genes. There was no linkage disequilibrium between these genes in male PD and control groups. The frequency of common haplotypes from MAO-A and -B was different in PD and control group (p = 0.02). Our data indicate that MAO-A and -B may play a role in susceptibility to PD in our sample.

    Funded by: NIAAA NIH HHS: AA09515; NIMH NIH HHS: MH30312; NINDS NIH HHS: NS07205, NS31001, NS32318, NS43351

    Genomics 2004;83;3;454-60

  • Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population.

    Díaz-Anzaldúa A, Joober R, Rivière JB, Dion Y, Lespérance P, Richer F, Chouinard S, Rouleau GA and Montreal Tourette Syndrome Study Group

    McGill University Health Centre, Montreal, Quebec, Canada.

    Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (chi(2) TDT =4.93, 1 df, P=0.026) and the putative 'high-activity' alleles of the MAO-A promoter VNTR polymorphism (chi(2) TDT =7.124, 1 df P=0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.

    Molecular psychiatry 2004;9;3;272-7

  • The FAD binding sites of human monoamine oxidases A and B.

    Edmondson DE, Binda C and Mattevi A

    Department of Biochemistry and Chemistry, Rollins Research Center, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322-3050, USA. dedmond@bimcore.emory.edu

    The structural details of the interactions of the covalent 8alpha-S-cysteinyl-FAD with the protein moiety in monoamine oxidase B (MAO B) based on the MAO B crystal structure are described. The dinucleotide is bound to the protein in an extended conformation with the majority of the bonds to the protein identified as hydrogen bonds with amino acid side chains, amide bonds, and water molecules. Since those amino acids interacting with the FAD are conserved in monoamine oxidase A (MAO A), it is proposed that the FAD binding site in MAO A is quite similar to that in MAO B. The redox-active isoalloxazine ring is buried in the protein without direct access to bulk solvent. An electrostatic interaction is observed between the anionic pyrophosphate moiety and Arg42. The normally flat oxidized flavin ring is in a bent, puckered conformation in the MAO B binding site which is suggested to contribute to its reactivity in catalysis. This structural information is then used to explain previous studies on flavin analog incorporation into either MAO B or into MAO A.

    Funded by: NIGMS NIH HHS: GM-29433

    Neurotoxicology 2004;25;1-2;63-72

  • Association analysis for MAOA gene polymorphism with long-latency auditory evoked potentials in healthy females.

    Yu YW, Tsai SJ, Hong CJ, Chen TJ and Yang CW

    Yu's Psychiatric Clinic, Kaohsiung, Taiwan, ROC.

    The components of auditory evoked potentials (AEPs) have been demonstrated to be heritable and to be influenced by different neurotransmitter activities such as serotonin or dopamine. Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the degradation of dopamine, serotonin and norepinephrine. We examined the potential association of the functional 30-bp repeat MAOA gene-linked polymorphism region (MAOA-LPR) in 234 normal young Chinese females. The results demonstrated that there is no association for MAOA-LPR polymorphism and AEP components. Our negative findings suggested that this genetic polymorphism does not play a major role in the modulation of AEPs in normal young females, but we could not exclude that other polymorphisms of the MAOA gene affect AEP components. Further exploration of the other polymorphisms of the MAOA gene and multiple interactions of the polymorphisms in various neurotransmitter systems may be needed in future studies.

    Neuropsychobiology 2004;50;4;288-91

  • Family-based association study between the monoamine oxidase A gene and obesity: implications for psychopharmacogenetic studies.

    Camarena B, Santiago H, Aguilar A, Ruvinskis E, González-Barranco J and Nicolini H

    Departamento de Genética Psiquiátrica, Instituto Nacional de Psiquiatría Ramón de la Fuente México DF, México DF, México. camare@imp.edu.mx

    Family studies have reported that obesity has a strong heritable component. It has been suggested that a neurotransmitter dysfunction could be involved in mental disorders and obesity; therefore, candidate genes in psychiatric disorders could be a risk factor for obesity. We investigated the association between the monoamine oxidase A (MAO-A) gene and obesity. Fifty obese subjects and their parents were included in the study. Two polymorphisms designated EcoRV and upstream variable number tandem repeats of the MAO-A gene were analysed using polymerase chain reaction. For analysis of the families, the transmission disequilibrium test (TDT) was applied. The TDT analysis of the EcoRV polymorphism showed in obese subjects with a body mass index (BMI) >/=35 kg/m(2) a preferential transmission of the low activity-related allele (chi(2)(TDT) = 8.0, p = 0.005). Our findings may provide evidence of a candidate gene involved in obese subjects with a BMI >/=35 kg/m(2).

    Neuropsychobiology 2004;49;3;126-9

  • Polymorphisms in the serotonin transporter and monoamine oxidase A genes and their relationship to personality traits measured by the Temperament and Character Inventory and NEO Five-Factor Inventory in healthy volunteers.

    Samochowiec J, Syrek S, Michał P, Ryzewska-Wódecka A, Samochowiec A, Horodnicki J, Zakrzewska M and Kucharska-Mazur J

    Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland. samoj@sci.pam.szczecin.pl

    The associations between 5-HTT-linked polymorphic region (5-HTT-LPR), monoamine oxidase A (MAOA)-LPR and the dimensions of temperament evaluated using the Temperament and Character Inventory (TCI) and NEO Five-Factor Inventory (NEO-FFI) were studied. One hundred healthy volunteers (without psychiatric disorders) were recruited to represent a cross-section of the population of Szczecin (Poland) in terms of sex, age and education. No associations between 5-HTT-LPR and the TCI harm avoidance dimension and between 5-HTT-LPR and the NEO-FFI neuroticism dimension were found. Males carrying the 3-VNTR MAOA gene variant (209 bp) had significantly lower values on the NEO-FFI openness dimension (p = 0.039) and obtained higher scores on the subdimension 3 of the TCI reward dependence (RD3), i.e. attachment vs. detachment (p = 0.005). Individuals carrying the 'short' variant of 5-HTT-LPR had lower values on the reward dependence dimension and the RD4 subdimension (dependence vs. independence) than individuals not carrying the 'short' variant (p = 0.039 and p = 0.011, respectively). Females carrying the 'short' variant had lower values on NS1 (exploratory excitability vs. stoic rigidity) and RD4 (dependence vs. independence) than those not carrying the variant (p = 0.042 and 0.043, respectively). The obtained level of significance with respect to the observed associations between 5-HTT-LPR and the reward dependence scales and subscales and between 5-HTT-LPR and the NS1 subscale are too weak for further interpretation. Our results do not confirm the hypothesis that there is a simple correlation between single gene polymorphisms and a personality trait measured by the TCI and NEO-FFI scales.

    Neuropsychobiology 2004;50;2;174-81

  • Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia.

    Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimäki T and Leinonen E

    Department of Psychiatry, Tampere University Hospital, Tampere, Finland. ari.illi@uta.fi

    Biogenic amine synthesis and degradation are involved in the pathogenesis of schizophrenia. Catechol-O-methyltransferase and monoamine oxidase enzymes are important agents in the metabolic inactivation of these neurotransmitters (ie, dopamine, serotonin, and norepinephrine). Functional polymorphism in the catechol-O-methyltransferase and monoamine oxidase A genes causes variation in enzyme activities. We investigated the relationship of catechol-O-methyltransferase Val158Met and monoamine oxidase A promoter repeat polymorphism with response to conventional neuroleptic treatment in schizophrenia.Ninety-four schizophrenic patients formed 2 different study populations. The responders had experienced a fair and steady response to conventional neuroleptics. The nonresponders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age-matched and gender-matched blood donors. Genotyping of the catechol-O-methyltransferase and monoamine oxidase A genes was performed by polymerase chain reaction.Forty-three percent of the nonresponders had a low activity catechol-O-methyltransferase genotype compared with 16% of the responders (P = 0.009). Monoamine oxidase A genotype alone did not differ significantly between the groups. Moreover, the risk of having both low-activity catechol-O-methyltransferase and monoamine oxidase A genotypes was over 6 times more common (odds ratio = 6.16, P = 0.03) in the nonresponders compared with responders. The whole population of patients with schizophrenia did not differ from the controls.The low-activity catechol-O-methyltransferase genotype may be associated with unsatisfactory drug response to conventional neuroleptics or alternatively be involved in a subset of schizophrenics. The role of monoamine oxidase A genotype seems to be additive in this respect.

    Journal of clinical psychopharmacology 2003;23;5;429-34

  • Association of autism severity with a monoamine oxidase A functional polymorphism.

    Cohen IL, Liu X, Schutz C, White BN, Jenkins EC, Brown WT and Holden JJ

    Departments of Psychology, Cytogenetics and Human Genetics, Staten Island, New York 10314, USA. Ira.Cohen@omr.state.ny.us

    A functional polymorphism (the upstream variable-number tandem repeat region, or uVNTR) in the monoamine oxidase A (MAOA) promoter region has been reported to be associated with behavioral abnormalities as well as increased serotonergic responsivity. We examined the relation between MAOA-uVNTR alleles and the phenotypic expression of autism in 41 males younger than 12.6 years of age. Children with the low-activity MAOA allele had both lower intelligence quotients (IQ) and more severe autistic behavior than children with the high-activity allele. In follow-up testing of 34 of the males at the 1-year time-point, those with the low-activity allele showed a worsening in IQ but no change in the severity of their autistic behavior. We conclude that functional MAOA-uVNTR alleles may act as a genetic modifier of the severity of autism in males.

    Clinical genetics 2003;64;3;190-7

  • Structural comparison of human monoamine oxidases A and B: mass spectrometry monitoring of cysteine reactivities.

    Hubalek F, Pohl J and Edmondson DE

    Department of Biochemistry and the Microchemical and Proteomics Facility, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    Monoamine oxidases (MAO) A and B are approximately 60-kDa outer mitochondrial membrane flavoenzymes catalyzing the degradation of neurotransmitters and xenobiotic arylalkyl amines. Despite 70% identity of their amino acid sequences, both enzymes exhibit strikingly different properties when exposed to thiol-modifying reagents. Human MAO A and MAO B each contain 9 cysteine residues (7 in conserved sequence locations). MAO A is inactivated by N-ethylmaleimide (NEM) much faster (tau(1/2) = approximately 3 min) than MAO B (tau(1/2) = approximately 8 h). These differences in thiol reactivities are also demonstrated by monitoring the NEM modification stoichiometries by electrospray mass spectrometry. Inactivation of either enzyme with acetylenic inhibitors results in alterations of their thiol reactivities. Cys5 and Cys266 were identified as the only residues modified by biotin-derivatized NEM in clorgyline-inactivated MAO A and pargyline-inactivated MAO B, respectively. The x-ray structure of MAO B (Binda, C., Newton-Vinson, P., Hubalek, F., Edmondson, D. E., and Mattevi, A. (2002) Nat. Struct. Biol. 9, 22-26) shows that Cys5 is located on the surface of the molecule opposite to the membrane-binding region. Cys266 in MAO A is predicted to be located in the same region of the molecule. These thiol residues are also modified by biotin-derivatized NEM in the mitochondrial membrane-bound MAO A and MAO B. This study shows that the MAO A structure is "more flexible" than that of MAO B and that clorgyline and pargyline inactivation of MAO A and B, respectively, increases the structural stability of both enzymes. No evidence is found for the presence of disulfide bonds in either enzyme, contrary to a previous suggestion.

    Funded by: NCRR NIH HHS: NCRR-02878, NCRR-12878, NCRR-13948; NIGMS NIH HHS: GM-29433

    The Journal of biological chemistry 2003;278;31;28612-8

  • Association analysis of MAOA and COMT with neuroticism assessed by peers.

    Eley TC, Tahir E, Angleitner A, Harriss K, McClay J, Plomin R, Riemann R, Spinath F and Craig I

    Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, United Kingdom. t.eley@iop.kcl.ac.uk

    There are several reported associations between depressive disorders, panic disorder, and obsessive-compulsive disorder (OCD) and a variety of polymorphisms in the monoamine oxidase A (MAOA) gene. Associations have also been reported between the catechol-O-methyltransferase (COMT) gene and both OCD and bipolar depression. However, the role of these markers has not been explored for the personality trait of neuroticism (N), a normally distributed quantitative trait, which is highly genetically correlated with anxiety and depression and may be a vulnerability to either type of disorder. We explored the possible role of MAOA, COMT, and their interaction on N using a selected extremes design. From a sample of 2,085 individuals, each assessed for N by two independent peers rather than using self-report questionnaires, we selected 57 individuals from the top 10% of scores, and 62 individuals from the bottom 10%. Using selected extreme low subjects as the controls, rather than an unselected control group gives roughly twice the power of a standard case-control design. We typed a functional variable number tandem repeat (VNTR) in the MAOA gene promoter, and a functional polymorphism in the coding region of the COMT gene. Two novel alleles in the MAOA VNTR were identified on the basis of their size, and their structure examined by sequencing analysis. We found weak evidence for association with COMT genotype, when the females and males were considered separately, and for MAOA genotype in males only. There was no significant interaction between COMT and MAOA.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;120B;1;90-6

  • Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes.

    Pooley EC, Houston K, Hawton K and Harrison PJ

    University Department of Psychiatry and Centre for Suicide Research, Warneford Hospital, University of Oxford.

    Background: There is a heritable component to suicidal behaviour, encouraging the search for the associated risk alleles. Given the putative role of the 5-HT (5-hydroxytryptamine; serotonin) system in suicidal behaviour, serotonergic genes are leading candidates. In particular, several studies have reported an association with variants in the tryptophan hydroxylase (TPH) gene.

    Method: We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects. The polymorphisms were TPH (A779C), 5-HT transporter (5-HTT, LPR S/L), monoamine oxidase A (MAOA G941T), 5-HT1B receptor (HTR1B G861C), 5-HT2A receptor (HTR2A T102C), and 5-HT2C receptor (HTR2C Cys23Ser). Genotyping was done using polymerase chain reaction (PCR)-based assays. The primary analyses compared allele and genotype frequencies between cases and controls. There were a limited number of planned secondary analyses within the deliberate self-harm group.

    Results: The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1.38, 95% CI 1.02-1.88; P = 0.03). None of the other polymorphisms was associated with deliberate self-harm. Within the deliberate self-harm group there were no associations with impulsivity, suicide risk, lifetime history of depression, or family history of deliberate self-harm.

    Conclusions: Our data extend the evidence that allelic variation in the TPH gene is a risk factor for deliberate self-harm. No evidence was found to implicate the other polymorphisms.

    Psychological medicine 2003;33;5;775-83

  • Mapping the genetic variation of executive attention onto brain activity.

    Fan J, Fossella J, Sommer T, Wu Y and Posner MI

    Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, NY 10021, USA.

    Brain imaging data have repeatedly shown that the anterior cingulate cortex is an important node in the brain network mediating conflict. We previously reported that polymorphisms in dopamine receptor (DRD4) and monoamine oxidase A (MAOA) genes showed significant associations with efficiency of handling conflict as measured by reaction time differences in the Attention Network Test (ANT). To examine whether this genetic variation might contribute to differences in brain activation within the anterior cingulate cortex, we genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the ANT. In each of the two genes previously associated with more efficient handling of conflict in reaction time experiments, we found a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The results demonstrate how genetic differences among individuals can be linked to individual differences in neuromodulators and in the efficiency of the operation of an appropriate attentional network.

    Funded by: NIMH NIH HHS: 1 F32 MH64360-01A1, F32 MH064360

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;12;7406-11

  • Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAO-A gene in Han Chinese males.

    Lu RB, Lin WW, Lee JF, Ko HC and Shih JC

    Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. rblu@tpts5.seed.net.tw

    Background: Recent studies on the genetics of alcoholism have suggested an association between antisocial alcoholism and the MAO-A gene. However, previous studies have failed to include subjects with antisocial personality disorder without alcoholism even though there is a high comorbidity between antisocial personality disorder and alcoholism. Consequently, the finding of an association between the MAO-A gene and alcoholism or antisocial personality disorder seems tenuous. In Taiwan, about 70% of the Han Chinese population have the ADH2*2 allele and 50% show ALDH2*1/*2 or ALDH2*2/*2 genotypes, which offer protection against drinking behavior and the risk of developing alcoholism. Thus, it is possible to recruit individuals with antisocial personality disorder but without alcoholism in Taiwan. Therefore, association studies of alcoholism or antisocial personality disorder in Chinese may be more reliable if pure antisocial alcoholics, pure antisocial personality disorders, and normal controls as MAO-A gene are examined.

    Methods: In this study, the associations among antisocial alcoholism, antisocial personality disorder, and the uVNTR and EcoRV polymorphisms of the MAO-A gene, both individually and as a haplotype, were investigated among male adults recruited from jails in Taipei. A total of 129 Chinese Han males were studied, including 41 with antisocial personality disorder with alcoholism, 50 with antisocial personality disorder but without alcoholism, and 38 without either disorder as a jail control group. The diagnoses of alcohol dependence and antisocial personality disorder were made according to DSM-IV criteria. In addition, 77 normal controls were collected from the community.

    Results: Strong linkage disequilibrium was found for the uVNTR and EcoRV variants of MAO-A gene in each study group.

    Conclusions: No significant association was observed between these two polymorphisms and antisocial personality disorder with alcoholism, either individually or for the haplotype, or for antisocial personality disorder without alcoholism. Thus, neither antisocial alcoholism nor antisocial personality disorder was associated with the genetic variants of MAO-A gene.

    Funded by: NIMH NIH HHS: R01 MH37020, R37 MH39085

    Alcoholism, clinical and experimental research 2003;27;6;889-93

  • [Relationship between the Fnu4HI site polymorphism of monoamine oxidase A gene and Parkinson's disease].

    Jiang XH, Yang H, Yang JF, Dong XM, Xu QY and Chen B

    Institute for Neuroscience, Capital University of Medical Sciences, Beijing, 100054 PR China.

    Objective: To study the association between the polymorphism of human monoamine oxidase type A (MAO-A) gene and Parkinson's disease(PD).

    Methods: Fnu4HI restriction fragment length polymorphism(RFLP) and PCR-RFLP were used to detect the mutation of MAO-A gene. The frequencies of alleles and genotypes at the MAO-A Fnu4HI locus on the X chromosome in different PD group were compared with those of the control group.

    Results: It was found that the frequencies of G allele in the patients with PD and controls were 0.613 and 0.527 respectively, P=0.039 "the frequencies of TT genotype were 0.303 and 0.415(P=0.014), and the frequencies of GG genotype were 0.564 and 0.451 respectively(P=0.021). When the patients were divided into two groups by age-onset, significant difference in the allelic and genotypic frequencies was observed only between early-onset PD group and control group. And when the PD patients were grouped by sex, significant difference was observed only between male PD group and male control group (the frequencies of G allele being 0.669 and 0.500 respectively, P=0.005).

    Conclusion: This study revealed significant differences between PD group and control group in allelic and genotypic frequencies. The findings supported the hypothesis about an association between MAO-A gene and PD, suggesting that age at onset of PD and gender predisposition might be related to the putative association, and Fnu4HI SNP be a risk factor for PD.

    Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2003;20;3;211-4

  • Association between a promoter variant in the monoamine oxidase A gene and schizophrenia.

    Jönsson EG, Norton N, Forslund K, Mattila-Evenden M, Rylander G, Asberg M, Owen MJ and Sedvall GC

    Department of Clinical Neuroscience, Psychiatry Section, HUBIN project, Karolinska Institute and Hospital, R5:00, SE-171 76 Stockholm, Sweden. erikj@ks.se

    Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p<0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated.

    Schizophrenia research 2003;61;1;31-7

  • Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism.

    Arbelle S, Benjamin J, Golin M, Kremer I, Belmaker RH and Ebstein RP

    Unit for Child Psychiatry, Soroka Hospital, Beer Sheva, Israel.

    Objective: Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)).

    Method: The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms.

    Results: Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms.

    Conclusions: This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.

    The American journal of psychiatry 2003;160;4;671-6

  • Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder.

    Hemmings SM, Kinnear CJ, Niehaus DJ, Moolman-Smook JC, Lochner C, Knowles JA, Corfield VA and Stein DJ

    MRC/US Centre for Molecular and Cellular Biology, University of Stellenbosch, P.O. Box 19063, 7505, Tygerberg, South Africa. smjh@sun.ac.za

    There is increasing evidence that the aetiology of obsessive-compulsive disorder (OCD) has a marked genetic component, although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. This study investigated the role of attractive candidate genes in the serotonergic and dopaminergic pathways in the development of OCD. The distribution of selected polymorphic variants in the serotonin receptor type 2A and 1Dbeta (5-HT(2A), 5-HT(1Dbeta)), dopamine transporter (DAT), dopamine receptor type 4 (DRD4) and monoamine-oxidase A (MAO-A) genes were analysed in 71 OCD cases and 129 control individuals in the genetically homogeneous Afrikaner population, by means of case-control association studies. Although no statistically significant genotypic or allelic associations were detected, the data yielded interesting preliminary results that warrant further discussion and investigation.

    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 2003;13;2;93-8

  • Serotonin-related gene polymorphisms and central nervous system serotonin function.

    Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK and Siegler IC

    Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3926, Durham, NC 27710, USA. redfordw@acpub.duke.edu

    Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnover-indexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)-in a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicity x genotype interaction (P=0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gender x genotype interaction (P=0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P=0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.

    Funded by: NCRR NIH HHS: M01RR30; NHLBI NIH HHS: P01HL36587; NIMH NIH HHS: K05MH79482

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2003;28;3;533-41

  • Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression.

    Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Möller HJ and Dahmen N

    Department of Psychiatry and Psychotherapy, University of Mainz, Mainz, Germany.

    This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over-represented in patients suffering from GAD (chi(2) = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;117B;1;1-6

  • Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis.

    Parsian A, Cloninger CR, Sinha R and Zhang ZH

    Birth Defects Center, Department of Molecular and Cellular Biology, University of Louisville Health Sciences Center, Louisville, Kentucky, USA. parsian@louisville.edu

    Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO-A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO-A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO-A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two-loci and three-loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO-A may play a role in the development of alcoholism but the gene effect is very small.

    Funded by: NIAAA NIH HHS: AA09515; NIMH NIH HHS: MH30312

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;117B;1;46-50

  • Monoamine oxidase polymorphisms and smoking behaviour in Japanese.

    Ito H, Hamajima N, Matsuo K, Okuma K, Sato S, Ueda R and Tajima K

    Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya Aichi 464-8681, Japan. hidemi@aichi-cc.jp

    Although nicotine dependence is one of the primary reasons why smokers cannot quit smoking, nicotine cannot explain all of the psychopharmacological effects of tobacco smoke. Accumulating evidence points to potent inhibition of monoamine oxidase (MAO) which metabolizes neurotransmitters relating to additive behaviour. We have therefore investigated the association between smoking behaviour and MAO ( variable number of tandem repeat in the promoter region and A644G) polymorphisms. The genotypes were examined in 504 Japanese outpatients (217 men and 287 women) who visited Aichi Cancer Centre Hospital. The age-adjusted odds ratios (aORs) were estimated by a logistic model. Among males, we did not find a significant association of the smoking habit with either of the polymorphisms. The median Fargastrom test for nicotine dependence (FTND) score among male current smokers was significantly higher with than without the 4-repeat allele (5.8 and 4.7, respectively). The aOR of FTND 6 versus FTND 6 was 2.72 (95% confidence interval 1.13-6.50) for males with the 4-repeat allele. Among females, the aOR of being current smokers compared to never smokers was 0.49 (0.26-0.93) for individuals with the 4-repeat allele. Our results indicate that the polymorphisms of influence the smoking habit for female, as well as the nicotine dependence and smoking initiation for male smokers. These findings among male smokers support the view that MAO affects a smokers' requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some individuals find it difficult to stop smoking.

    Pharmacogenetics 2003;13;2;73-9

  • Association analysis of monoamine oxidase A and attention deficit hyperactivity disorder.

    Lawson DC, Turic D, Langley K, Pay HM, Govan CF, Norton N, Hamshere ML, Owen MJ, O'Donovan MC and Thapar A

    Department of Psychologycal Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.

    Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder. Although the causes of ADHD are unknown, dopaminergic, serotonergic and nor-adrenergic pathways have been strongly implicated. Monoamine Oxidase A (MAOA) is involved in the degradation of all three of these neurotransmitters and therefore has been suggested as a strong candidate gene for ADHD. Animal and human studies have implicated MAOA and 5-HT in impulsive and aggressive behavior. We therefore additionally postulated that MAOA might be associated with a subtype of ADHD where aggressive and impulsive features are especially prominent. We have tested this hypothesis by genotyping two polymorphisms (the 30-bp VNTR in the promoter and the Fnu4HI 941T-->G) in MAOA that are associated with altered MAOA function. Our sample consisted of 171 British Caucasian children 6-16 years of age fulfilling DSM-III R, DSM-IV or ICD-10 criteria for ADHD/Hyperkinetic Disorder. Using case control analysis and then the TDT, no association was found between these two MAOA polymorphisms and ADHD. Case control analysis of the VNTR showed an association with a subgroup of children with comorbid conduct problems (OR = 2.0, 95% CI = 1.09, 3.5), and TDT analysis indicated a statistical trend toward association. Our findings highlight the importance of phenotype definition and the need for the MAOA VNTR to be further examined.

    Funded by: Medical Research Council: G1000632

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;116B;1;84-9

  • Early-onset schizophrenia and dopamine-related gene polymorphism.

    Iwata Y, Matsumoto H, Minabe Y, Osada N, Nakamura K, Sekizawa T, Suzuki K, Sekine Y, Takei N and Mori N

    Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

    Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;116B;1;23-6

  • No association between a polymorphism in the promoter region of the MAOA gene with antisocial personality traits in alcoholics.

    Koller G, Bondy B, Preuss UW, Bottlender M and Soyka M

    Psychiatrische Klinik und Poliklinik der LMU München, Nussbaumstrasse 7, 80336 München, Germany.

    Aims: We analysed the MAOAuVNTR functional polymorphism in the promoter region of the X-chromosomal monoamine oxidase A (MAOA) gene. Genotypes with three-repeat alleles were reported to be associated with antisocial as well as impulsive traits.

    Methods: The repeat number (3-5) of the MAOA polymorphism was determined in 169 male alcoholic subjects and 72 controls of German descent. Behavioural and personality traits were evaluated using the Brown-Goodwin Assessment for History of Lifetime Aggression, the Buss Durkee Hostility Inventory, as well as the Barrat Impulsiveness Score. A median split in Brown-Goodwin, Buss Durkee Irritability, Buss Durkee Assault and Barrat Impulsiveness Score was conducted.

    Results: High scores were found, i.e. 47.9% in Brown-Goodwin, 65.7% in Buss Durkee Irritability, 63.3% in Buss Durkee Assault and 59.8% in Barrat Impulsiveness Scale, indicating high impulsiveness, irritability and antisocial behaviour. Based on the results of these questionnaires, we detected no significant differences between the frequency of the three-repeat allele and high or low scores in alcoholics and controls.

    Conclusions: Taken together, these findings suggest that the three-repeat allele of the MAOAuVNTR 30-bp polymorphism is not associated with impulsive and aggressive personality traits.

    Alcohol and alcoholism (Oxford, Oxfordshire) 2003;38;1;31-4

  • Monoamine oxidase A gene polymorphism, 5-HT 2A receptor gene polymorphism and incidence of nausea induced by fluvoxamine.

    Yoshida K, Naito S, Takahashi H, Sato K, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Suzuki T and Ohkubo T

    Department of Psychiatry, Akita University School of Medicine, Akita, Japan. cxw01076@nifty.com

    Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a -1438G/A polymorphism in the promoter region of the 5-HT(2A) gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50-200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.

    Neuropsychobiology 2003;48;1;10-3

  • Inhibitors alter the spectrum and redox properties of monoamine oxidase A.

    Ramsay RR and Hunter DJ

    Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9AL, UK. rrr@st-andrews.ac.uk

    Monoamine oxidase A (MAO A) catalyses the oxidation of both neurotransmitter and ingested amines. The mechanism of catalysis involves the covalently bound FAD cofactor. Although substrates and inhibitors alter the thermodynamic and kinetic properties of the flavin, how the ligands interact with the flavin is unknown. This work characterises the spectral changes that occur on inhibitor binding to MAO A and examines how the binding influences the flavin. The inhibitors, D-amphetamine, harmine, tetrindole, and befloxatone all induce similar (but not identical) changes in the spectrum of MAO A, consistent with stacking of inhibitor with the flavin in the active site. D-Amphetamine, harmine, and tetrindole stabilise the semiquinone form of FAD during reduction of MAO A by dithionite and no further reduction of these inhibitor-MAO A complexes has been observed. In contrast, semiquinone is never observed during reduction of the befloxatone-MAO A complex. Instead, partial reduction directly to the FADH(2) form occurs extremely slowly. Thus, inhibitor binding has a strong, structure-dependent influence on the environment of the flavin that alters its electronic properties.

    Biochimica et biophysica acta 2002;1601;2;178-84

  • Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder.

    Yoshida K, Naito S, Takahashi H, Sato K, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K and Otani K

    Department of Psychiatry, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. cxw01076@nifty.com

    Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.

    Progress in neuro-psychopharmacology & biological psychiatry 2002;26;7-8;1279-83

  • Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease.

    Kelada SN, Costa-Mallen P, Costa LG, Smith-Weller T, Franklin GM, Swanson PD, Longstreth WT and Checkoway H

    Department of Environmental Health, University of Washington, Seattle 98195, USA. skelada@u.washington.edu

    We tested for gender-specific interactions between smoking and genetic polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1 or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's disease (PD) cases and 296 age- and gender-matched controls. The odds ratios (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13-0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18-2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001, P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV or DRD2 Taq1B genotypes. These results suggest that a strong gender difference exists with respect to the modifying effect of MAO-B genotype on the smoking association with PD.

    Funded by: NIEHS NIH HHS: ES04696, ES07032, ES07033, ES10750

    Neurotoxicology 2002;23;4-5;515-9

  • Polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers: seeking confirmation of the association in a follow-up study.

    Johnstone EC, Clark TG, Griffiths SE, Murphy MF and Walton RT

    Cancer Research UK General Practice Research Group, Institute of Health Sciences, Oxford, UK.

    Pharmacogenetics 2002;12;7;585-7

  • Role of genotype in the cycle of violence in maltreated children.

    Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A and Poulton R

    Medical Research Council Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK.

    We studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children's sensitivity to environmental insults.

    Funded by: NIMH NIH HHS: MH45070, MH49414

    Science (New York, N.Y.) 2002;297;5582;851-4

  • [The EcoR V polymorphism of human monoamine oxidase A is not associated with idiopathic Parkinson's disease in a Shanghai Han population].

    Xie H, Wang X, Hao Y, Tang G, Xu L, Wu Q, Chen L and Ren D

    Department of Neurology, Changhai Hospital, the Second Military Medical University, Shanghai, 200433 P.R.China. dmren@fudan.edu.cn

    Objective: To explore the distribution of monoamine oxidase A (MOA-A) EcoRV polymorphism in Shanghai Han population and its possible role in the risk for Parkinson's disease(PD).

    Methods: The MAO-A gene EcoRV polymorphism was detected with PCR-RFLP method in 110 PD patients and 182 healthy controls, furthermore, statistical analysis was performed to investigate association between EcoR V polymorphism and PD onset.

    Results: (1)Remarkable difference in MAO-A EcoR V polymorphic distribution has been observed between Shanghai Han population and that in North America. (2) Neither allelic frequency nor genotypic frequency in PD cases differs significantly from that in healthy controls regardless of data from male or female subclass.

    Conclusion: There may be racial difference in the distribution of the human MAO-A EcoR V (C/T) polymorphism, but the present research does not support the association between this variant and susceptibility to PD in Chinese Han population of Shanghai area.

    Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2002;19;4;329-31

  • Evidence for a genetic association between monoamine oxidase A and restless legs syndrome.

    Desautels A, Turecki G, Montplaisir J, Brisebois K, Sequeira A, Adam B and Rouleau GA

    Centre d'étude du sommeil, Hôpital du Sacré-Coeur de Montréal and Centre de recherche en sciences neurologiques, Université de Montréal, Quebec, Canada.

    Background: Impairment in the central dopaminergic system has been consistently suggested as an etiologic factor in restless legs syndrome (RLS).

    Objective: To investigate a possible role for the MAOA and MAOB genes in RLS using a population-based association study.

    Methods: In addition to a dinucleotide repeat located within the second intron of the MAOB gene, a functional variable number of tandem repeat (VNTR) polymorphism recently identified in the MAOA gene promoter region was examined, using 96 extensively characterized patients and 200 control subjects matched for ethnic background. The relationship between variation at these loci and several clinical features was also considered.

    Results: Pertaining to the MAOA gene, females with the high activity allele had a greater risk (OR: 2.0; 95% CI: 1.06 to 3.77) of being affected with RLS than females carrying the low activity alleles. The authors did not observe this association among the male subjects (OR: 0.98; 95% CI: 0.31 to 3.14). Interestingly, females carrying the high transcription alleles showed a longer sleep onset latency (U = 163.5; p = 0.015) and exhibited a higher movement index during the Suggested Immobilization Test (Student's t-test = -2.02; p = 0.048). No differences were observed regarding the MAOB gene in our sample.

    Conclusions: The high activity allele of the MAOA gene may represent a modifying factor involved in the severity of RLS manifestations in females.

    Funded by: NINDS NIH HHS: 1R01NS37754-01A1

    Neurology 2002;59;2;215-9

  • Association of monoamine oxidase A gene polymorphism with Alzheimer's disease and Lewy body variant.

    Takehashi M, Tanaka S, Masliah E and Ueda K

    Laboratory of Molecular Clinical Chemistry, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.

    The association between (GT)n dinucleotide repeats in monoamine oxidase gene loci, monoamine oxidase A (MAOA) and B (MAOB), and Parkinson's disease (PD), Alzheimer's disease (AD), and Lewy body variant (LBV) of AD were determined. MAOA-GT polymorphisms were significantly associated with pure AD and LBV. MAOA-GT allele 113 was excessively represented in pure AD and LBV compared with controls. Furthermore, the frequency of females homozygous for MAOA-GT allele 113 was higher in pure AD and LBV than controls by 2.79- and 2.77-fold, respectively. In contrast, there was no association between MAOA-GT or MAOB-GT polymorphisms and PD. These results suggest that polymorphisms within the MAOA gene may have implication in AD pathology shared by pure AD and LBV.

    Funded by: NIA NIH HHS: AG5131

    Neuroscience letters 2002;327;2;79-82

  • Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis.

    Norton N, Kirov G, Zammit S, Jones G, Jones S, Owen R, Krawczak M, Williams NM, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK. Nortonn@Cardiff.ac.uk

    Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia.

    American journal of medical genetics 2002;114;5;491-6

  • High activity-related allele of MAO-A gene associated with depressed suicide in males.

    Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D and Hrdina PD

    Institute of Mental Health Research at Royal Ottawa Hospital and University of Ottawa, 1145 Carling Ave., Ontario K1Z 7K4, Canada.

    Abnormalities in brain monoamine oxidase A activity have been implicated in the pathogenesis of depressive illness and suicidal behavior. The present investigation was to determine whether there is an association between MAO-A gene polymorphism and depressed suicide. The EcoRV polymorphism in MAO-A gene with alleles associated with enzyme activity was studied in postmortem brain samples from 44 depressed suicide victims and 92 control subjects of the same ethnic background. We have found significant differences in genotype/allele distribution between depressed suicide victims and controls in males (p = 0.012) but not in females or the total sample. The odds ratio (OR) for the high activity-related allele of the MAO-A gene associated with depressed suicide in males was 3.1. Our finding suggests that MAO-A may be a susceptibility gene in depressed male suicide victims. The results thus provide further evidence that genetic factors can modulate risk for depression, suicide or both by influencing monoaminergic activity in sexually dimorphic manner.

    Neuroreport 2002;13;9;1195-8

  • Moclobemide response in depressed patients: association study with a functional polymorphism in the monoamine oxidase A promoter.

    Müller DJ, Schulze TG, Macciardi F, Ohlraun S, Gross MM, Scherk H, Neidt H, Syagailo YV, Grässle M, Nöthen MM, Maier W, Lesch KP and Rietschel M

    Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. d.mueller@uni-bonn.de

    Pharmacopsychiatry 2002;35;4;157-8

  • Analysis of conserved active site residues in monoamine oxidase A and B and their three-dimensional molecular modeling.

    Geha RM, Chen K, Wouters J, Ooms F and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089-9121, USA.

    Monoamine oxidase (MAO) is a key enzyme responsible for the degradation of serotonin, norepinephrine, dopamine, and phenylethylamine. It is an outer membrane mitochondrial enzyme existing in two isoforms, A and B. We have recently generated 14 site-directed mutants of human MAO A and B, and we found that four key amino acids, Lys-305, Trp-397, Tyr-407, and Tyr-444, in MAO A and their corresponding amino acids in MAO B, Lys-296, Trp-388, Tyr-398, and Tyr-435, play important roles in MAO catalytic activity. Based on the polyamine oxidase three-dimensional crystal structure, it is suggested that Lys-305, Trp-397, and Tyr-407 in MAO A and Lys-296, Trp-388, and Tyr-398 in MAO B may be involved in the non-covalent binding to FAD. Tyr-407 and Tyr-444 in MAO A (Tyr-398 and Tyr-435 in MAO B) may form an aromatic sandwich that stabilizes the substrate binding. Asp-132 in MAO A (Asp-123 in MAO B) located at the entrance of the U-shaped substrate-binding site has no effect on MAO A nor MAO B catalytic activity. The similar impact of analogous mutants in MAO A and MAO B suggests that these amino acids have the same function in both isoenzymes. Three-dimensional modeling of MAO A and B using polyamine oxidase as template suggests that the overall tertiary structure and the active sites of MAO A and B may be similar.

    Funded by: NIMH NIH HHS: R01 MH037020, R01 MH037020-16, R01 MH37020, R37 MH039085, R37 MH039085-23, R37 MH39085

    The Journal of biological chemistry 2002;277;19;17209-16

  • Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.

    Cusin C, Serretti A, Lattuada E, Lilli R, Lorenzi C and Smeraldi E

    Department of Psychiatry, Vita-Salute University, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy.

    The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.

    American journal of medical genetics 2002;114;4;380-90

  • Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.

    Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C, Corradi B, Grieco G, Costa A, Santorelli F, Barale F, Nappi G and Smeraldi E

    Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Milan, Italy. serretti.alessandro@hsr.it

    Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5-HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO-A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family-based association approach. Both diagnoses and psychopathology were used for phenotype definitions. A total of 134 nuclear families with mood disorders, with probands affected by bipolar (n = 103) or major depressive (n = 58) disorders, were included in the study. All subjects were typed for the above-mentioned gene variants using polymerase chain reaction (PCR) technique. No significant transmission disequilibrium was found in the overall sample for any polymorphism. A separate analysis of bipolar subjects only, or the use of continuous psychopathologic traits as affectation status did not influence the observed results. Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders.

    American journal of medical genetics 2002;114;4;361-9

  • Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants.

    Serretti A, Lorenzi C, Lilli R, Mandelli L, Pirovano A and Smeraldi E

    Department of Psychiatry, Vita-Salute University, Fondazione Centro San Raffaele del Monte Tabor, Milan, Italy. serretti.alessandro@hsr.it

    We studied the possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein beta 3-subunit (Gbeta3) C825T. A total of 201 subjects affected by bipolar (n = 160) and major depressive (n = 41) disorder were followed prospectively for an average of 59.8 months and were typed for their gene variants using PCR techniques. COMT, MAO-A, and Gbeta3 variants were not associated with lithium outcome, even when possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment, and previous episodes were included in the model. The pathways influenced by those variants are not therefore involved with long-term lithium outcome in our sample.

    American journal of medical genetics 2002;114;4;370-9

  • Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients.

    Hamajima N, Saito T, Matsuo K, Suzuki T, Nakamura T, Matsuura A, Okuma K and Tajima K

    Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    This paper lists the genotype frequencies of 50 polymorphisms of 37 genes (ALDH2, ADRB2, ADRB3, COMT, CD36, CXCR2, CCND1, COX2, CYP2A6, CYP17, CYP19, IGF1, IL-1A, IL-1B, IL-1RN, IL-1R1, IL-6, IL-8, IL-10, LEP, Le, L-myc, MPO, MTR, MTHFR, MAO-A, NQO1, OGG1, p53, p73, Se, SRD5A2, TGF-B, TNF-A, TNF-B, XPD, and XRCC1) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients. Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers, 15 polymorphisms (CD36 A52C, CXCR2 C785T, CCND1 G870A, IGF1 C/T at intron 2 and G2502T, IL-1A 46-bp VNTR, IL-1R1 C-116T, IL-6 Ins/Del 17C, IL-8 A-278T and C74T, IL- 10 T-819C, LEP A-2548G, SRD5A2 2-bp VNTR, XPD Lys751Gln, and XRCC1 Arg399Gln) and six sets of combined genotype frequencies (IL-1B C-31T and IL-1A C-889T, IL-1B C-31T and IL-1RN 86-bp VNTR, IL-1B C-31T and IL-1R1 C-116T, TNF-A G-308A and TNF-B A252G, SRD5A2 Val89Leu and 2-bp VNTR, and XRCC1 Arg399Gln and XPD Lys751Gln) were reported in this paper for the first time for Japanese. Although microarray technology will produce this kind of information in near future, this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose.

    Journal of epidemiology 2002;12;3;229-36

  • No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides.

    Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y and Maeda K

    Department of Psychiatry and Neurology, Kobe University School of Medicine, Kobe, Japan.

    Monoamine oxidase A (MAOA) has been implicated in the control of aggression and/or impulsivity in humans and been involved in suicide. This gene has a functional polymorphism in which there is a variable number tandem repeat (VNTR) in the upstream region (MAOA-uVNTR). We hypothesized that MAOA dysfunction due to this polymorphism was associated with suicide genetically through the disinhibition of aggression and/or impulsivity. We performed an association study between completed suicides and the MAOA-uVNTR polymorphism. No significant difference in genotype distribution or allele frequencies was found between completed suicides and comparison groups either in males or females. These results show no evidence of an association between the MAOA-uVNTR polymorphism and completed suicides and suggest that MAOA is not involved in the susceptibility to suicide.

    American journal of medical genetics 2002;114;3;340-2

  • No association of the MAOA gene with alcoholism among Han Chinese males in Taiwan.

    Lu RB, Lee JF, Ko HC, Lin WW, Chen K and Shih JC

    Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. rblu@tpts5.seed.net.tw

    A positive association of MAOA polymorphisms with alcoholism has been demonstrated in certain recent studies, however, this association is not universally supported. The haplotype status of the MAOA gene polymorphisms could provide more information than alleles at a single site alone tested for an association with a complex, heterogeous disorder. This study examines whether there is an association between alcoholism and either a variable number of tandem repeat located upstream of the MAOA gene or an EcoRV functional polymorphism of the MAOA gene. These are analyzed both individually and as haplotypes. The study consisted of 214 subjects meeting DSM-IV criteria for alcoholism from northern Taiwan and 77 control individuals without history of alcoholism from Taipei. All of the subjects were Chinese Han males. For the two polymorphic sites, significant linkage disequilibrium occurred. No significant intergroup difference was observed between the two subject groups with respect to the allele frequencies for the two polymorphisms at the MAO locus tested both individually and as haplotypes. This finding suggests that no association exists between genetic variation at the MAOA locus and alcoholism in Chinese Han males.

    Funded by: NIMH NIH HHS: R01 MH37020, R37 MH39085

    Progress in neuro-psychopharmacology & biological psychiatry 2002;26;3;457-61

  • Analysis of monoamine oxidase A (MAOA) promoter polymorphism in Finnish male alcoholics.

    Saito T, Lachman HM, Diaz L, Hallikainen T, Kauhanen J, Salonen JT, Ryynänen OP, Karvonen MK, Syvälahti E, Pohjalainen T, Hietala J and Tiihonen J

    Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

    Alterations in monoamine oxidase A (MAOA) expression and enzyme activity may be associated with alcoholism and impulsive behavior. Therefore, functional polymorphisms in the MAOA gene would be good candidates to consider in the interindividual differences that exist in the susceptibility to alcoholism. One variant that has been considered as a candidate in alcoholism is a repeat polymorphism in the MAOA gene promoter. We analyzed a cohort of Finnish males with either type 1 or type 2 alcoholism, as well as controls, for differences in the distribution of MAOA promoter alleles. Based on other studies, we postulated that type 2 alcoholism, which is associated with antisocial behavior, but not type 1 alcoholism, would be correlated with the inheritance of the low promoter activity allele. However, we failed to find a difference in allele distribution in type 1 and type 2 alcoholics. In addition, there was no difference in the allele distribution when each group of alcoholics was compared with controls. However, when both groups of alcoholics were pooled and compared with controls, the difference in allele distribution reached a trend towards significance. Our results suggest a minimal association between the MAOA low activity promoter alleles and alcoholism, regardless of the presence or absence of antisocial behavior. Interestingly, approximately 3% of type 2 alcoholics were found to be heterozygous for the MAOA promoter polymorphism. Since MAOA is X-linked, the heterozygotes are probable cases of Klinefelter's syndrome (47,XXY) suggesting that X-chromosome aneuploidy may increase the risk for developing type 2 alcoholism.

    Psychiatry research 2002;109;2;113-9

  • [Investigation of monoamine oxidase gene restriction polymorphism in male populations of the Volga-Ural region].

    Gorbunova EV, Galeeva AR and Khusnutdinova EK

    Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Bashkortostan, Russia. ekkh@anrb.ru

    Restriction polymorphism at the monoamine oxidase A (MAO A) gene was typed in eight male populations of the Volga-Ural region (Bashkirs, Chuvashes, Tatars, Udmurts, Maris, Mordovians, Komis, and Russians inhabiting the Republic of Bashkortostan). Analysis of the MAO A alleles frequency distribution patterns did not reveal statistically significant differences between the Volga-Ural populations examined. The results obtained suggest genetic homogeneity of the populations described in respect of the polymorphic locus examined.

    Genetika 2002;38;3;419-21

  • High-level expression of human liver monoamine oxidase A in Pichia pastoris: comparison with the enzyme expressed in Saccharomyces cerevisiae.

    Li M, Hubálek F, Newton-Vinson P and Edmondson DE

    Department of Biochemistry, Emory University, Atlanta, Georgia 30322-3050, USA.

    The high-level expression, purification, and characterization of recombinant membrane-bound human liver monoamine oxidase A (MAO-A) in Pichia pastoris is described. Two liters of fermentation culture produces 1170 units (660 mg) of MAO-A. The enzyme is purified in a 35% yield, is homogeneous on denaturing gel electrophoresis, and exhibits a single species (60,512 +/- 6 Da) on electrospray mass spectrometry. It contains 1 mol of 8alpha-S-cysteinyl FAD/mole of enzyme and exhibits >95% functionality. In contrast, the Saccharomyces cerevisiae-expressed enzyme is partially processed by C-terminal serine removal as demonstrated by mass spectra. The amino termini of both P. pastoris- and S. cerevisiae-expressed MAO-A are acetylated on the N-terminal methionine. The steady-state kinetic properties of P. pastoris-expressed MAO-A are similar to those of S. cerevisiae-expressed MAO-A using the following substrates: phenethylamine, p-CF(3)-benzylamine, dopamine, serotonin, and kynuramine. Reductive titrations demonstrate that the recombinant enzyme is reduced by 1 mol of substrate or dithionite as expected for the two electron equivalents required for flavin reduction. Absorption and EPR spectra show no radical species in the resting enzyme while the anionic flavin radical is formed in 50% yield during the reductive titration with dithionite. These data demonstrate significant advantages in the heterologous expression of human MAO-A in P. pastoris compared with the published S. cerevisiae system in higher expression level (329 mg/L) and in a higher level of homogeneity of the isolated enzyme.

    Funded by: NCRR NIH HHS: NCRR-02878, NCRR-12878, NCRR-13948; NIGMS NIH HHS: GM-29433

    Protein expression and purification 2002;24;1;152-62

  • Monoamine oxidase expression and activity in human placentae from pre-eclamptic and normotensive pregnancies.

    Sivasubramaniam SD, Finch CC, Billett MA, Baker PN and Billett EE

    Department of Life Sciences, The Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK.

    A feature of pre-eclampsia is that circulating levels of maternal serotonin (5-hydroxytryptamine) are elevated and placental monoamine oxidase-A (MAO-A) activity, the major factor in the regulation of serotonin levels in pregnancy, is reduced. It is not known whether this is due to a reduced MAO-A protein content or a reduced catalytic turnover of the serotonin by MAO-A; this question has been addressed in the present work. Term placentae from normotensive and pre-eclamptic women were analysed for MAO-A specific mRNA expression (by semi-quantitative RT-PCR), MAO-A protein (by immunohistochemistry and quantitative ELISA, using a MAO-A specific monoclonal antibody), together with MAO activity (using [(3)H] labelled 5-hydroxytryptamine as substrate). Immunohistochemical analysis of placentae from both normotensive and pre-eclamptic women demonstrated that MAO-A protein is located in the cytoplasm of the placental syncytiotrophoblast layer, consistent with a mitochondrial location; no MAO-A protein was found in the nucleus. No MAO-B protein was detected in this placental layer, despite the presence of MAO-B mRNA. The results indicate that both total protein/g fresh weight and MAO-A protein/g fresh weight were approximately 40 per cent lower in pre-eclamptic than in normotensive placentae, but that there was no statistical difference in the expression of MAO-A mRNA in relation to GAPDH or actin mRNA or in MAO-A protein/mg total protein. However, MAO-A activity/g fresh weight was significantly reduced in pre-eclamptic placentae, in agreement with previous findings. This was found to be due to a 60 per cent reduction (P< 0.05) in the catalytic turnover (activity/molecule) of the enzyme. This study has therefore clearly shown that the expression of placental MAO-A specific mRNA and MAO-A protein are not specifically affected in pre-eclampsia, but that the catalytic efficiency of the expressed MAO-A enzyme in pre-eclamptic placentae is greatly reduced.

    Placenta 2002;23;2-3;163-71

  • Evidence for positive selection and population structure at the human MAO-A gene.

    Gilad Y, Rosenberg S, Przeworski M, Lancet D and Skorecki K

    Department of Molecular Genetics and the Crown Human Genome Center, The Weizmann Institute of Science, Rehovot 76100, Israel. yoav.gilad@weizmann.ac.il

    We report the analysis of human nucleotide diversity at a genetic locus known to be involved in a behavioral phenotype, the monoamine oxidase A gene. Sequencing of five regions totaling 18.8 kb and spanning 90 kb of the monoamine oxidase A gene was carried out in 56 male individuals from seven different ethnogeographic groups. We uncovered 41 segregating sites, which formed 46 distinct haplotypes. A permutation test detected substantial population structure in these samples. Consistent with differentiation between populations, linkage disequilibrium is higher than expected under panmixia, with no evidence of a decay with distance. The extent of linkage disequilibrium is not typical of nuclear loci and suggests that the underlying population structure may have been accentuated by a selective sweep that fixed different haplotypes in different populations, or by local adaptation. In support of this suggestion, we find both a reduction in levels of diversity (as measured by a Hudson-Kreitman-Aguade test with the DMD44 locus) and an excess of high frequency-derived variants, as expected after a recent episode of positive selection.

    Proceedings of the National Academy of Sciences of the United States of America 2002;99;2;862-7

  • A regulatory monoamine oxidase a promoter polymorphism and personality traits.

    Garpenstrand H, Norton N, Damberg M, Rylander G, Forslund K, Mattila-Evenden M, Gustavsson JP, Ekblom J, Oreland L, Bergman H, Owen MJ and Jönsson EG

    Department of Neuroscience, Uppsala University, Uppsala, Sweden. hakan.garpenstrand@neuro.uu.se

    Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5' untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

    Funded by: Medical Research Council: G9309834, G9810900

    Neuropsychobiology 2002;46;4;190-3

  • Concurrent positive association between pathological gambling and functional DNA polymorphisms at the MAO-A and the 5-HT transporter genes.

    Pérez de Castro I, Ibáñez A, Saiz-Ruiz J and Fernández-Piqueras J

    Genetics Unit, Department of Biology, Autonoma University, Madrid, Cantoblanco-Madrid, Spain. perezi01@med.nyu.edu

    Molecular psychiatry 2002;7;9;927-8

  • Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA).

    Manor I, Tyano S, Mel E, Eisenberg J, Bachner-Melman R, Kotler M and Ebstein RP

    Geha Mental Health Center, Petak Tikvah, Israel.

    Monoamine oxidase A (MAO A) is located on the X chromosome and metabolizes biogenic amines including dopamine, norepinephrine and serotonin. A functional promoter-region polymorphism of this gene has been described that has been studied in a number of mental illnesses but not in attention deficit hyperactivity disorder (ADHD). In the current study, we examined the MAO A promoter-region polymorphism initially in 133 triads and observed preferential transmission of the long alleles from 74 heterozygote mothers to ADHD probands (chi(2) = 4.37, P = 0.036, df = 1). We also examined the role of this polymorphism in a computerized continuous performance test, the TOVA. Significant differences were observed on errors of commission (chi(2) = 7.021, P = 0.008) and patients carrying the long MAO A allele made significantly more such errors. Errors of commission are a measure of impulsivity. However, following Ritalin (methylphenidate) administration the association between this polymorphism and errors of commission was markedly attenuated and no longer significant at the P < 0.05 level. We also analyzed the provisional association by the case-control design. A significant difference in allele frequency was observed between 110 male probands vs 202 male controls (Pearson chi(2) = 7.94, P = 0.047). Similarly results were obtained when 19 female probands were compared to female controls (genotype chi(2) = 21.28; P = 0.0032, 3 df and allele chi(2) = 30.88, P= 0.0007, 2 df). All three complementary approaches employed (family-based, case-control and quantitative trait design) suggest a role for the MAO A promoter-region polymorphism in conferring risk for ADHD in our patient population.

    Molecular psychiatry 2002;7;6;626-32

  • Substrates but not inhibitors alter the redox potentials of monoamine oxidases.

    Sablin SO and Ramsay RR

    Department of Biochemistry and Biophysics, University of California San Francisco, 94143, USA.

    The midpoint potentials for the reduction of the cysteinyl-flavin adenine dinucleotide (FAD) in monoamine oxidases (MAO) A and B in the absence and presence of ligands have been determined. Both MAO A and MAO B can be reduced chemically in two steps, the first generating a semiquinone spectrum and the second the spectrum of fully reduced FAD, each of which requires two electron equivalents. The midpoint potentials for the oxidized/semiquinone and semiquinone/reduced couples were -159+/-4 mV and -262+/-3 mV for MAO A and -167+/-4 mV and -275+/-3 mV for MAO B. After modification with a thiol reagent, direct reduction from the oxidized to fully reduced form was observed with no semiquinone and without change in the overall midpoint potential. In the presence of substrate, no semiquinone was formed, but the midpoint potential for full reduction of the flavin was positively shifted by up to 500 mV, depending on the substrate. This shift in potential could permit a more thermodynamically favorable transfer of electrons from the amine substrates to oxygen. In contrast, stable products and inhibitors did not cause a shift in potential and did not prevent the formation of semiquinone.

    Funded by: NHLBI NIH HHS: HL-16251

    Antioxidants & redox signaling 2001;3;5;723-9

  • MAO-A and COMT polymorphisms and gene effects in narcolepsy.

    Dauvilliers Y, Neidhart E, Lecendreux M, Billiard M and Tafti M

    Neurologie B, Hôpital Gui-de-Chauliac, Montpellier-France, France.

    Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.

    Molecular psychiatry 2001;6;4;367-72

  • Additional evidence that genetic variation of MAO-A gene supports a gender subtype in obsessive-compulsive disorder.

    Camarena B, Rinetti G, Cruz C, Gómez A, de La Fuente JR and Nicolini H

    Departamento de Genética Psiquiátrica, Instituto Nacional de Psiquiatría Ramón de la Fuente, México D.F., México. camare@neuroserver.imp-neuro.edu.mx

    Studies have recently reported a sexually dimorphic association between obsessive-compulsive disorder (OCD) and a polymorphism related with variations in MAO-A activity. These observations suggest the possibility of gender differences in genetic susceptibility for OCD. We thus reexamined the MAO-A/EcoRV polymorphism in a sample of 122 OCD patients and 124 healthy subjects. An excess of allele 1 in OCD females with major depression disorder was confirmed as previously reported. This difference was more strongly associated with OCD females than males in the total sample. Finally, we analyzed a sample of 51 OCD trios. Haplotype-based haplotype relative risk (HHRR) analysis of the inheritance of the MAO-A variants revealed in the female probands that 14 out of 19 transmitted the allele 1, providing significant evidence for an allelic association between OCD and MAO-A gene. In conclusion, our findings may provide molecular evidence to identify a clinically meaningful gender subtype. However, an effort should be made to replicate the analysis in larger samples of informative parents using strategies such as transmission disequilibrium test to allow definite conclusions.

    American journal of medical genetics 2001;105;3;279-82

  • Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders.

    Syagailo YV, Stöber G, Grässle M, Reimer E, Knapp M, Jungkunz G, Okladnova O, Meyer J and Lesch KP

    Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.

    Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population.

    American journal of medical genetics 2001;105;2;168-71

  • Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder.

    Schulze TG, Müller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grässle M, Papassotiropoulos A, Heun R, Nöthen MM, Maier W, Lesch KP and Rietschel M

    Department of Psychiatry, University of Bonn, Bonn, Germany. tschulze@uni-bonn.de

    Various polymorphisms of the X-chromosomal monoamine oxidase A (MAO-A) gene were investigated for association with affective disorders. However, none of the studied variants could consistently be associated with either major depressive or bipolar affective disorder. Recently, a positive association between panic disorder and a novel functional repeat polymorphism in the MAO-A gene promoter, with the longer alleles being more active, was reported. Since monoaminergic neurotransmission is supposed to play an important role in affective disorders, we investigated a potential association of this polymorphism with major depressive illness in a sample of 146 unrelated patients of German descent and a control group of 101 individuals with a negative life history for affective disorders. Similarly to the recent findings in panic disorder, we observed a significantly increased frequency of genotypes containing only long alleles in female patients with recurrent major depression in comparison with age- and sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801-803, 2000.

    American journal of medical genetics 2000;96;6;801-3

  • A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory.

    Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H, Mann MB, Dietz G, Saucier G and MacMurray JP

    Department of Medical Genetics, City of Hope Medical Center, Duarte, CA 91010, USA.

    Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410-416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways, and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence) and three character dimensions (cooperativeness, self-directedness, and self-transcendence) were added to form the temperament and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade-Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196; Comings DD, Gade-Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.

    Funded by: NIDA NIH HHS: R01-DA08417

    Clinical genetics 2000;58;5;375-85

  • Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic disorder.

    Sand P, Lesch KP, Catalano M, Bosi M, Syagailo YV, Okladnova O, Di Bella D, Maffei P, Heils A, Friess F, Politi E, Nöthen MM, Franke P, Stöber G, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Riederer P and Deckert J

    Department of Psychiatry, University of Würzburg, Füchsleinstr. 15, 97080 Würzburg, Germany. philipp.sand@mail.uni-wuerzburg.de

    Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.

    The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 2000;1;3;147-50

  • Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat.

    Denney RM, Koch H and Craig IW

    Department of Human Biological Chemistry and Genetics, Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston 77555-0650, USA. rdenney@utmb.edu

    Among fifteen male skin fibroblast cultures from eleven donors ranging in age from less than 1 year to 90 years old, the specific activity of monoamine oxidase A (MAO-A) differed 515-fold. Each culture had one of the two most common alleles (three or four 30-bp repeats) at the variable number tandem repeat locus positioned 1.2 kb upstream from MAOA exon 1 (uVNTR). The mean MAO-A activity in cultures with three uVNTR repeats was significantly lower than that in cultures with four repeats (1.6 +/- 1.1 and 13 +/- 12 nmol/h per milligram, respectively; P=0.032). MAO-A expression was confined to a cell sub-population varying from 0.5% to 90% of cells in different cultures. The mean specific activity in MAO-A+ cells (whole culture specific activity divided by the proportion of immunopositive cells) was lower for cultures with three repeats than for those with four (7.2 +/- 3.1 and 23.9 +/- 9.5 nmol/h per milligram protein, respectively; P=0.0013), with no overlap in activity between genotypes. Finding lower MAO-A activity in cultures with three uVNTR repeats compared to those with four is consistent with published evidence that MAO-A promoter constructs bearing three repeats have lower transcriptional activity in transfected neuroblastoma and choriocarcinoma cells. The uVNTR genotype may be a common genetic determinant of significant individual differences in oxidizing capacity for critical MAO-A substrates, which include serotonin, norepinephrine, and tyramine.

    Human genetics 1999;105;6;542-51

  • Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.

    Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A and Sugano S

    International and Interdisciplinary Studies, The University of Tokyo, Japan.

    Using 'oligo-capped' mRNA [Maruyama, K., Sugano, S., 1994. Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 138, 171-174], whose cap structure was replaced by a synthetic oligonucleotide, we constructed two types of cDNA library. One is a 'full length-enriched cDNA library' which has a high content of full-length cDNA clones and the other is a '5'-end-enriched cDNA library', which has a high content of cDNA clones with their mRNA start sites. The 5'-end-enriched library was constructed especially for isolating the mRNA start sites of long mRNAs. In order to characterize these libraries, we performed one-pass sequencing of randomly selected cDNA clones from both libraries (84 clones for the full length-enriched cDNA library and 159 clones for the 5'-end-enriched cDNA library). The cDNA clones of the polypeptide chain elongation factor 1 alpha were most frequently (nine clones) isolated, and more than 80% of them (eight clones) contained the mRNA start site of the gene. Furthermore, about 80% of the cDNA clones of both libraries whose sequence matched with known genes had the known 5' ends or sequences upstream of the known 5' ends (28 out of 35 for the full length-enriched library and 51 out of 62 for the 5'-end-enriched library). The longest full-length clone of the full length-enriched cDNA library was about 3300 bp (among 28 clones). In contrast, seven clones (out of the 51 clones with the mRNA start sites) from the 5'-end-enriched cDNA library came from mRNAs whose length is more than 3500 bp. These cDNA libraries may be useful for generating 5' ESTs with the information of the mRNA start sites that are now scarce in the EST database.

    Gene 1997;200;1-2;149-56

  • Mutational analysis of the human MAOA gene.

    Tivol EA, Shalish C, Schuback DE, Hsu YP and Breakefield XO

    Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.

    The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention of genetic variations in the MAOA gene. In the present study variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing a mRNA or genomic DNA in 40 control males with > 100-fold variations of MAO-A activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys --> arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions.

    Funded by: NIMH NIH HHS: MH52416; NINDS NIH HHS: NS21921

    American journal of medical genetics 1996;67;1;92-7

  • The promoter of the human monoamine oxidase A gene.

    Denney RM

    Department of Human Biological Chemistry and Genetics, Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston 77555, USA.

    Monoamine oxidase (MAO) A (EC 1.4.3.4) oxidizes norepinephrine and serotonin and is expressed in a cell type-specific manner. Evidence that MAO A deficient males in a large Dutch kindred suffer from mild mental retardation and occasional episodes of impulsive-aggressive behavior makes it important to understand how the human MAO A promoter is regulated. Workers in multiple laboratories have isolated and characterized protein-coding sequences of the human MAO A gene and the DNA region where mRNA synthesis is initiated. After summarizing our published findings concerning where transcription of the human MAO A gene is initiated, I summarize representative results of transient expression assays aimed at assessing whether some potential gene regulatory agents affect the expression of luciferase from MAO A promoter reporter constructs when transfected into a mouse L cell line which expresses MAO A. These studies revealed no specific regulatory effects of serum, dexamethasone or a stable cyclic-AMP analogue on the human MAO A promoter introduced.

    Funded by: NINDS NIH HHS: NS19543

    Progress in brain research 1995;106;57-66

  • A new look at the promoter of the human monoamine oxidase A gene: mapping transcription initiation sites and capacity to drive luciferase expression.

    Denney RM, Sharma A, Dave SK and Waguespack A

    Department of Human Biological Chemistry and Genetics, Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston 77555.

    Monoamine oxidase (MAO) A (EC 1.4.3.4) oxidizes norepinephrine and serotonin and is expressed in a cell type-specific manner. Recent evidence that MAO A-deficient males in a large Dutch kindred suffer from mild mental retardation and occasional episodes of impulsive aggressive behavior makes it important to understand how the human MAO A promoter is regulated. Conventional primer extension analyses of MAO A mRNA in earlier studies predicted incorrect transcription initiation sites for the human MAO A promoter. Reverse transcription and polymerase chain reaction (PCR) readily detected MAO A mRNA initiated 5' to -135 bp but not 5' to -226 bp (5' to the ATG initiation codon). PCR-assisted primer extension and RNase protection assays reveal that most MAO A mRNA is initiated between -30 and -40, which resembles a eukaryotic initiator element. Depending on the tissue source, a minor, variable proportion of MAO A mRNAs is initiated more distally at approximately -95 and -136, within the more proximal of two 90-bp GC-rich tandem repeats. Genomic DNA segments spanning -4 to -200 and -465 or -935, but not -4 to -82, drive robust luciferase expression in mammalian cells. We conclude that (a) the primary transcription initiation site occurs at a putative initiator (lnr) element located between -30 and -40, with a minor, tissue-specific proportion of additional initiation near -95 and -136; and (b) MAO A-luciferase reporter constructs that contained all the known transcription initiation sites exhibited no evidence for inhibitory cis elements between -200 and at least -935. The apparent inhibitory activity previously reported for sequences 5' to the most proximal PvuII site may have resulted from the use of partial promoter constructs that omitted the putative lnr element.

    Funded by: NINDS NIH HHS: NS19543

    Journal of neurochemistry 1994;63;3;843-56

  • Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.

    Maruyama K and Sugano S

    Institute of Medical Science, University of Tokyo, Japan.

    We have devised a method to replace the cap structure of a mRNA with an oligoribonucleotide (r-oligo) to label the 5' end of eukaryotic mRNAs. The method consists of removing the cap with tobacco acid pyrophosphatase (TAP) and ligating r-oligos to decapped mRNAs with T4 RNA ligase. This reaction was made cap-specific by removing 5'-phosphates of non-capped RNAs with alkaline phosphatase prior to TAP treatment. Unlike the conventional methods that label the 5' end of cDNAs, this method specifically labels the capped end of the mRNAs with a synthetic r-oligo prior to first-strand cDNA synthesis. The 5' end of the mRNA was identified quite simply by reverse transcription-polymerase chain reaction (RT-PCR).

    Gene 1994;138;1-2;171-4

  • Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.

    Brunner HG, Nelen M, Breakefield XO, Ropers HH and van Oost BA

    Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

    Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.

    Funded by: NINDS NIH HHS: NS 21921

    Science (New York, N.Y.) 1993;262;5133;578-80

  • Site-directed mutagenesis of monoamine oxidase A and B: role of cysteines.

    Wu HF, Chen K and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.

    Nine cysteines are found in the deduced amino acid sequences of both human liver monoamine oxidase (MAO)-A and MAO-B. The role of these cysteine residues in MAO-A and -B catalytic activity was studied by site-directed mutagenesis, whereby each cysteine residue was converted to serine. The wild-type and mutant cDNAs were then transiently transfected into COS cells and assayed for MAO-A and -B catalytic activity using 5-[3H]hydroxytryptamine and [14C]phenylethylamine, respectively, as substrates. Catalytic activities were retained in seven MAO-A cysteine to serine mutants (mutations at residues 165, 210, 266, 306, 321, 323, and 398) and in six MAO-B cysteine to serine mutants (mutations at residues 5, 172, 192, 297, 312, and 389). Kinetic parameters (Km) of these mutants were also similar to those of the wild-type enzymes, indicating that these cysteines are not necessary for enzymatic activity. Substitution of MAO-A Cys-374 and -406 and MAO-B Cys-156, -365, and -397 with serine resulted in complete loss of MAO-A and -B catalytic activity. The loss of catalytic activity was not due to unsuccessful transfection of the mutants, as indicated by either Northern blot or Western blot analysis. The loss of catalytic activity in the MAO-A Ser-406 and MAO-B Ser-397 mutants may be due to the prevention of covalent binding of the enzyme to the cofactor FAD, which is necessary for catalytic activity. The loss of catalytic activity of MAO-A Ser-374 and MAO-B Ser-156 and -365 suggests that these cysteines are important for catalytic activity, but whether they are involved in forming the active site or are important for the appropriate conformation of MAO-A and -B remains to be studied.

    Funded by: NIMH NIH HHS: K05 MH 00796, R01 MH 37020, R37 MH 39085

    Molecular pharmacology 1993;43;6;888-93

  • Promoter organization and activity of human monoamine oxidase (MAO) A and B genes.

    Zhu QS, Grimsby J, Chen K and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.

    Monoamine oxidase A and B (MAO A and B) play important roles in the metabolism of biogenic and dietary amines and are encoded by two genes derived from a common ancestral gene. The promoter regions for human MAO A and B genes have been characterized using a series of 5' flanking sequences linked to a human growth hormone reporter gene. When these constructs were transfected into NIH3T3, SHSY-5Y, and COS7 cells, the maximal promoter activity for MAO A was found in a 0.14 kilobase (kb) PvuII/DraII fragment (A0.14) and in a 0.15 kb PstI/NaeI fragment (B0.15) for MAO B. Both fragments are GC-rich, contain potential Sp1 binding sites, and are in the region where the MAO A and B 5' flanking sequences share the highest identity (approximately 60%). However, the organization of the transcription elements is distinctly different between these two promoters. Fragment A0.14 consists of three Sp1 elements, all in reversed orientations, and lacks a TATA box. Two of the Sp1 sites are located within the downstream 90 base pair (bp) direct repeat, and the third is located at the 3' end of the upstream 90 bp direct repeat. Fragment B0.15 contains an Sp1-CACCC-Sp1-TATA structure; deletion of any of these elements reduced promoter activity. Additional Sp1 sites, CACCC elements, CCAAT boxes, and direct repeats (four 30 bp direct repeats in MAO A and two 29 bp direct repeats in MAO B) are found in farther-upstream sequences of both genes (1.27 kb for MAO A and mostly in 0.2 kb for MAO B). Inclusion of these sequences decreased promoter activity. The different promoter organization of MAO A and B genes provides the basis for their different tissue- and cell-specific expression.

    Funded by: NIMH NIH HHS: K05 MH00796, R01 MH37020, R37 MH39085

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1992;12;11;4437-46

  • Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19-6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain.

    Saura J, Kettler R, Da Prada M and Richards JG

    F. Hoffmann-La Roche Ltd., Pharma Division, Basel, Switzerland.

    Monoamine oxidases A and B (MAO-A and MAO-B) oxidatively deaminate neurotransmitter and xenobiotic amines. Since the cellular localization of the isoenzymes in the CNS and peripheral organs determines to a large extent which substrate has access to which isoenzyme, knowledge of their tissue distribution and cellular localization is essential. Here we describe how reversible and selective inhibitors of MAO-A and MAO-B [Ro 41-1049 and Ro 19-6327 (lazabemide), respectively] can be used, as tritiated radioligands, to map the distribution and abundance of the enzymes in microscopic regions of the rat CNS and peripheral organs, and human brain by quantitative enzyme radioautography. The in vitro binding characteristics of both radiolabeled inhibitors revealed them to be selective, high-affinity ligands for the respective enzymes. KD and Bmax values for 3H-Ro 41-1049 in rat cerebral cortex were 10.7 nM and 7.38 pmol/mg protein, respectively, and for 3H-Ro 19-6327 were 18.4 nM and 3.45 pmol/mg protein, respectively. In accordance with their potencies as enzyme inhibitors, binding to MAO-A and MAO-B was competitively inhibited by clorgyline (IC50 = 1.4 nM) and L-deprenyl (selegiline; IC50 = 8.0 nM), respectively. The capacities of various rat and human tissues to bind the radioligands correlated extremely well with their corresponding enzyme activities. As revealed by the respective binding assays, the distribution and abundance of MAO-A and MAO-B in the tissues investigated differed markedly. MAO-A was most abundant in the locus coeruleus, paraventricular thalamus, bed nucleus of the stria terminalis, median habenular nucleus, ventromedial hypothalamus, raphe nuclei, solitary tract nucleus, inferior olives, interpeduncular nucleus, claustrum, and numerous peripheral tissues, including liver, vas deferens, heart, superior cervical ganglion, and exocrine and endocrine pancreas. In contrast, MAO-B was most abundant in the ependyma, circumventricular organs, olfactory nerve layer, periventricular hypothalamus, cingulum, hippocampal formation, raphe nuclei, paraventricular thalamus, mammillary nuclei, cerebellar Bergmann glia cells, liver, posterior pituitary, renal tubules, and endocrine pancreas. The cellular localization of the isoenzymes in both rat and human brain differs markedly and does not reflect the distribution of the presumed natural substrates, for example, absence of MAO-A in serotoninergic neurons. Indeed, the present evidence suggests that, whereas MAO-A is found in noradrenergic and adrenergic neurons, MAO-B occurs in astrocytes, serotoninergic neurons, as well as ventricular cells, including most circumventricular organs. The physiological roles of the enzymes are discussed in the light of these findings, some of which were unexpected.(ABSTRACT TRUNCATED AT 400 WORDS)

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1992;12;5;1977-99

  • Mode of action and characteristics of monoamine oxidase-A inhibition by moclobemide.

    Cesura AM, Kettler R, Imhof R and Da Prada M

    Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

    The mode of interaction of the reversible monoamine oxidase-A (MAO-A) inhibitor moclobemide with the enzyme was investigated. The inhibition of rat brain or human placenta MAO-A by moclobemide showed an initial competitive phase, with a relatively low affinity (KI = 0.2-0.4 mM). However, the potency of the inhibitor was increased with incubation time. The time-dependent component of the association of moclobemide with MAO-A followed pseudo-first order kinetics. In contrast to mechanism-based inhibitors, no indication for adduct or product formation was detected after incubation of moclobemide with the enzyme. Even though some aspects of the moclobemide interaction with MAO-A are still not completely elucidated, this compound seems to have the characteristics of a slow-binding inhibitor.

    Psychopharmacology 1992;106 Suppl;S15-6

  • Genetic and physical mapping around the properdin P gene.

    Coleman MP, Murray JC, Willard HF, Nolan KF, Reid KB, Blake DJ, Lindsay S, Bhattacharya SS, Wright A and Davies KE

    Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, England.

    A CA repeat has been found on the human X chromosome within 16 kb of the gene encoding properdin P factor (PFC) and has been shown to be a highly informative marker. Two more polymorphic CA repeats were found in a cosmid containing DXS228. The CA repeats, and other markers from proximal Xp, were mapped genetically in CEPH families and the likely order of markers was established as Xpter-(DXS7, MAO-A, DXS228)-(PFC, DXS426)-(TIMP, OATL1)-DXS255-Xcen. This places PFC in the region Xp11.3-Xp11.23, thus refining previous in situ hybridization data. Two yeast artificial chromosomes (YACs) (440 and 390 kb) contain both PFC and DXS426, and one of them (440 kb) also contains TIMP. This confirms the genetic order TIMP-(PFC, DXS426). PFC and TIMP are located on the same 100-kb SalI/PvuI fragment of the 440-kb YAC. Given the genetic orientation of TIMP and (PFC, DXS426), this YAC can now serve as a starting point for directional walking toward disease genes located in Xp11.3-Xp11.2 such as retinitis pigmentosa (RP2) and Wiskott-Aldrich syndrome.

    Funded by: NIDCR NIH HHS: DE08556; NIGMS NIH HHS: GM40864; Wellcome Trust

    Genomics 1991;11;4;991-6

  • Structure of the human gene for monoamine oxidase type A.

    Chen ZY, Hotamisligil GS, Huang JK, Wen L, Ezzeddine D, Aydin-Muderrisoglu N, Powell JF, Huang RH, Breakefield XO, Craig I et al.

    Department of Biochemistry, University of Oxford, UK.

    Monoamine oxidases, type A and type B, d96 are principal enzymes for the degradation of biogenic amines, including catecholamines and serotonin. These isozymes have been implicated in neuropsychiatric disorders. Previously, cDNA clones for both MAO-A and MAO-B have been sequenced and the genes encoding them have been localized to human chromosome Xp11.23-Xp11.4. In this work, we isolated human genomic clones spanning almost all the MAOA gene from cosmid and phage libraries using a cDNA probe for MAO-A. Restriction mapping and sequencing show that the human MAOA gene extends over 70 kb and is composed of 15 exons. The exon structure of human MAOA is similar to that described by others for human MAOB. Exon 12 (bearing the codon for cysteine, which carries the covalently bound FAD cofactor) and exon 13 are highly conserved between human MAOA and MAOB genes (92% at the amino acid level). Earlier work revealed two species of MAO-A mRNA, 2.1 kb and 4.5-5.5 kb. We now report on further cDNA isolation and sequencing, which demonstrates that the longer message has an extension of 2.2 kb in the 3' noncoding region. This extended region is contained entirely within exon 15. The two messages therefore appear to be generated by the use of two alternative polyadenylation sites. Results from the present work should facilitate the mutational analysis of functional domains of MAO-A and MAO-B. Knowledge of the gene structure will also help in evaluating the role of genetic variations in MAO-A in human disease through the use of genomic DNA, which is more accessible than the RNA, as a template for PCR-amplification and sequencing.

    Funded by: NIAAA NIH HHS: R01 AA 07643; NINDS NIH HHS: NS21921; PHS HHS: A08683

    Nucleic acids research 1991;19;16;4537-41

  • Kinetic mechanism of monoamine oxidase A.

    Ramsay RR

    Department of Biochemistry and Biophysics, University of California, San Francisco 94143.

    Steady-state kinetic data for monoamine oxidase A in crude extracts suggest an exclusively ping-pong mechanism, in contrast to those for monoamine oxidase B, which indicate alternate mechanisms involving either a binary or ternary complex. In this study, with use of purified monoamine oxidase A, steady-state data for the inhibition by D-amphetamine of the oxidation of primary amines indicate the possibility of a ternary complex mechanism for monoamine oxidase A also. Stopped-flow studies demonstrate that the rate of reoxidation of reduced enzyme is enhanced by substrates but not by the product, 1-methyl-4-phenylpyridinium. Thus, for the A enzyme, the ternary complex with substrate, but not product, is reoxidized at a faster rate than the free, reduced enzyme. For both the A and B forms of monoamine oxidase, the mechanism is determined by competition between alternate pathways on the basis of the relative rate constants and dissociation constants.

    Funded by: NHLBI NIH HHS: HL-16251

    Biochemistry 1991;30;18;4624-9

  • Human monoamine oxidase A and B genes exhibit identical exon-intron organization.

    Grimsby J, Chen K, Wang LJ, Lan NC and Shih JC

    Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.

    Monoamine oxidases A and B [MAOA and MAOB; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] play important roles in the metabolism of neuroactive, vasoactive amines and the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Human MAOA and MAOB genes isolated from X chromosome-specific libraries span at least 60 kilobases, consist of 15 exons, and exhibit identical exon-intron organization. Exon 12 codes for the covalent FAD-binding-site and is the most conserved exon; the MAOA and MAOB exon 12 products share 93.9% peptide identity. These results suggest that MAOA and MAOB are derived from duplication of a common ancestral gene and provide insight on the structural/functional relationship of the enzyme products.

    Funded by: NIMH NIH HHS: KO5 MH00796, R01 MH 37020, R37MH39085

    Proceedings of the National Academy of Sciences of the United States of America 1991;88;9;3637-41

  • Localization of human monoamine oxidase-A gene to Xp11.23-11.4 by in situ hybridization: implications for Norrie disease.

    Levy ER, Powell JF, Buckle VJ, Hsu YP, Breakefield XO and Craig IW

    Genetics Laboratory, Department of Biochemistry, Oxford, United Kingdom.

    A cDNA for the neurotransmitter-degrading enzyme monoamine oxidase-A (MAO-A) has been assigned by in situ hybridization to the human X chromosome and subregionally localized to Xp11.23-11.4. As restriction fragments detected by this probe are deleted in some patients with Norrie disease, this assignment provides confirmation of the localization of the disease.

    Funded by: NINDS NIH HHS: NS21921

    Genomics 1989;5;2;368-70

  • Monoamine oxidase A from human placenta and monoamine oxidase B from bovine liver both have one FAD per subunit.

    Weyler W

    Veterans Administration Medical Center, Molecular Biology, San Francisco, CA 94121.

    I present the first clear evidence that the protein: FAD ratio in human monoamine oxidase A and bovine monoamine oxidase B has an upper limit of 65 kDa and 57 kDa per FAD, respectively. To now it had been assumed that the protein: FAD ratio was 100-120 kDa to 1 FAD and that there was one FAD per two subunits which were assumed to be of the same size. For the present work the purity of monoamine oxidase A and monoamine oxidase B was improved over that previously achieved. Protein was determined by quantitative amino acid analysis and FAD content was measured by spectrophotometric titration of SDS-denatured enzyme with NaS2O4 standardized against riboflavin. The cause of the previous misassignment of the protein: FAD ratio was judged as having been due to the use of impure enzyme preparations. Knowledge of the correct protein: FAD ratio is important in devising cloning strategies for this enzyme, in understanding its structure, function, mechanism, and in the studies of its biosynthesis.

    The Biochemical journal 1989;260;3;725-9

  • Partial amino acid sequence analysis of human placenta monoamine oxidase A and bovine liver monoamine oxidase B.

    Chen SA and Weyler W

    Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010.

    We have prepared peptide maps from human placenta monoamine oxidase type A (MAO-A) and bovine monoamine oxidase type B (MAO-B) and determined the amino acid sequences of 21 of these peptides. These sequences have been compared to the cDNA deduced amino acid sequences of human MAO-A and -B. A result of special interest is the identification of two sets of MAO-A peptides which have sequences different from those deduced from cDNA sequences. This observation is consistent with the notion that MAO-A may be composed of at two subunits which are similar but not identical in primary amino acid sequence.

    Funded by: NCI NIH HHS: CA33572; NIMH NIH HHS: MH42462; NINDS NIH HHS: NS25786

    Biochemical and biophysical research communications 1988;156;1;445-50

  • Structural features of human monoamine oxidase A elucidated from cDNA and peptide sequences.

    Hsu YP, Weyler W, Chen S, Sims KB, Rinehart WB, Utterback MC, Powell JF and Breakefield XO

    Molecular Neurogenetics Division, E. K. Shriver Center, Waltham, MA 02254.

    Monoamine oxidase (MAO), an important enzyme for the degradation of amine neurotransmitters, has been implicated in neuropsychiatric illness. The amino acid sequence for one form of the enzyme, MAO-A, has been deduced from human cDNA clones and verified against proteolytic peptides. The covalent binding site for the flavin adenine dinucleotide (FAD) cofactor is near the C-terminal region. The presence of features characteristic of the ADP-binding fold suggests that the N-terminal region is also involved in the binding of FAD. These cDNAs should facilitate the study of the structure, function, and intracellular targeting of MAO, as well as the analysis of its expression in normal and pathological states.

    Funded by: NICHD NIH HHS: HD00824; NINDS NIH HHS: NS21921, NS25786

    Journal of neurochemistry 1988;51;4;1321-4

  • cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties.

    Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, Seeburg PH and Shih JC

    Center for Molecular Biology, University of Heidelberg, F.R.G.

    The monoamine oxidases play a vital role in the metabolism of biogenic amines in the central nervous system and in peripheral tissues. Using oligonucleotide probes derived from three sequenced peptide fragments, we have isolated cDNA clones that encode the A and B forms of monoamine oxidase and have determined the nucleotide sequences of these cDNAs. Comparison of the deduced amino acid sequences shows that the A and B forms have subunit molecular weights of 59,700 and 58,800, respectively, and have 70% sequence identity. Both sequences contain the pentapeptide Ser-Gly-Gly-Cys-Tyr, in which the obligatory cofactor FAD is covalently bound to cysteine. Based on differences in primary amino acid sequences and RNA gel blot analysis of mRNAs, the A and B forms of monoamine oxidase appear to be derived from separate genes.

    Funded by: NIMH NIH HHS: MH 37020, MH 39085, MH 42729

    Proceedings of the National Academy of Sciences of the United States of America 1988;85;13;4934-8

  • Immunological uniqueness of human monoamine oxidases A and B: new evidence from studies with monoclonal antibodies to human monoamine oxidase A.

    Kochersperger LM, Waguespack A, Patterson JC, Hsieh CC, Weyler W, Salach JI and Denney RM

    Monoamine oxidase (EC 1.4.3.4; MAO) is the primary enzyme responsible for the intraneuronal degradation of biogenic amines in the central nervous system. An understanding of the physiological significance of the functional and regulatory differences between the two forms of the enzyme, MAOs A and B, would be facilitated by the availability of antibodies specific for the two forms of the enzyme. We previously isolated and characterized a monoclonal antibody (MAO B-1C2, previously designated MAO-1C2) which binds human MAO B but not A. We describe here four new monoclonal antibodies (designated MAO A-3C9, A-4F10, A-7B10, and A-7E10) which were elicited to highly purified MAO A from human placenta and which, in the presence of antimouse IgG and Staphylococcus aureus, immunoprecipitate greater than 90% of the catalytically active purified MAO A. MAO A-3C9 appears to have a lower affinity for purified MAO A than the other three antibodies and does not immunoprecipitate either MAO A or MAO B from human platelets or from Triton X-100 extracts of human placental and liver mitochondria. MAO A-4F10, A-7B10, and A-7E10 immunoprecipitate catalytically active MAO A from Triton X-100 extracts of human placental and liver mitochondria, but not catalytically active MAO B from either pletelets or from Triton X-100 extracts of human liver mitochondria. Collectively, these anti-MAO monoclonal antibodies reveal unique epitopes on human MAO A not shared by MAO B, and at least one epitope on MAO B not shared by MAO A. These immunochemical differences support the hypothesis that MAO A and MAO B are different proteins, presumably isozymes.

    Funded by: NINDS NIH HHS: NS-14222, NS-19543

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1985;5;11;2874-81

  • The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions.

    O'Carroll AM, Fowler CJ, Phillips JP, Tobbia I and Tipton KF

    The deamination of dopamine has been studied in seven regions of human brain. Both A and B forms of the enzyme were found to be active towards this substrate. The ratio of activities of MAO-A: MAO-B was found to vary considerably from brain region to brain region, from about 1:1 for the cerebral and cerebellar cortex to about 1:2 for the pons and medulla oblongata. Enzyme titration studies and comparisons of the substrate specificities of MAO-A and MAO-B across the brain indicated that dopamine was metabolised by the same MAO active centres as other monoamines. In the cerebral cortex, the Km values of MAO-A and -B towards dopamine were found to be 210 and 230 microM, respectively, indicating that the relative contributions of these two forms towards the oxidation of this substrate will not be significantly affected by changes in its concentration.

    Naunyn-Schmiedeberg's archives of pharmacology 1983;322;3;198-202

  • Human liver MAO-A and MAO-B separated by immunoaffinity chromatography with MAO-B-specific monoclonal antibody.

    Denney RM, Fritz RR, Patel NT and Abell CW

    A monoclonal antibody was used to prepare immunoaffinity columns that efficiently bind monoamine oxidase B activity but not monoamine oxidase A activity from detergent extracts of human liver mitochondria. The only discrete polypeptide component that eluted from affinity columns with potassium thiocyanate migrated in sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 59,000, as expected for human monoamine oxidase B. These results support the hypothesis that there is an intrinsic structural difference between monoamine oxidase A and B and demonstrate that immunoaffinity chromatography can physically resolve the two enzyme species in liver extracts.

    Funded by: NIMH NIH HHS: NIMH-34757

    Science (New York, N.Y.) 1982;215;4538;1400-3

  • Studies on beta-phenylethylamine deamination by human placental monoamine oxidase.

    Oguchi K, Kobayashi S, Uesato T and Kamijo K

    Kinetical properties of human placental monoamine oxidase (MAO) were investigated in studies on inhibitors and mixed substrates. MAO activity was determined by a radioisotopic assay. Lineweaver-Burk plots were linear at higher and lower concentrations of PEA, whereas at intermediate substrate concentrations, a downward curving plot was obtained. The Km values of the low- and high-affinity sites for PEA deamination were estimated. Studies with mixed substrates showed that 5-HT was a competitive inhibitor and tyramine a mixed-type inhibitor of deamination at high concentrations of PEA, whereas both were non-competitive inhibitors at lower concentrations of PEA. After pre-incubation of human placental mitochondrial preparations with deprenyl, Lineweaver-Burk plots were completely linear, and the Km value was the same as that obtained at low concentrations of PEA in the absence of deprenyl. Tyramine and 5-HT were competitive inhibitors of PEA deamination by deprenyl-treated MAO. From these results it is concluded that there are two kinds of MAO with high- and low-affinity sites for PEA in mitochondria of human placenta, corresponding to type B and A Mao, and that tyramine, 5-HT and PEA share a substrate-binding site on type A Mao, while tyramine and 5-HT bind to a site on type B MAO that is different from the PEA binding site.

    Japanese journal of pharmacology 1981;31;1;7-14

Gene lists (7)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000011 G2C Homo sapiens Human clathrin Human orthologues of mouse clathrin coated vesicle genes adapted from Collins et al (2006) 150
L00000012 G2C Homo sapiens Human Synaptosome Human orthologues of mouse synaptosome adapted from Collins et al (2006) 152
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.