G2Cdb::Human Disease report

Disease id
D00000166
Name
Schizophrenia
Nervous system disease
yes

Genes (20)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002000 MYO5A
myosin VA (heavy chain 12, myoxin)
Y (16508936) Single nucleotide polymorphism (SNP) Y
G00001313 GRM5
glutamate receptor, metabotropic 5
Y (11326300) Microinsertion (MI) Y
G00001313 GRM5
glutamate receptor, metabotropic 5
Y (11326300) Repeat polymorphism (RP) Y
G00001369 HOMER1
homer homolog 1 (Drosophila)
Y (12815733) Single nucleotide polymorphism (SNP) N
G00001881 L1CAM
L1 cell adhesion molecule
Y (11425011) Single nucleotide polymorphism (SNP) Y
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (11109007) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (11326295) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (11326295) Deletion (D) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (11326295) Microinsertion/deletion (MI/D) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12210277) Microdeletion/insertion (MD/I) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12363394) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12454527) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12679240) Single nucleotide polymorphism (SNP) Y
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12707933) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (15841096) Single nucleotide polymorphism (SNP) ?
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (9800222) Repeat polymorphism (RP) Y
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (11353443) Repeat polymorphism (RP) N
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (15276701) Repeat polymorphism (RP) Y
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (11807411) Repeat polymorphism (RP) N
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (15999343) Single nucleotide polymorphism (SNP) Y
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (15318030) Polymorphism (P) N
G00002208 AKAP5
A kinase (PRKA) anchor protein 5
Y (16434481) Copy Number Polymorphism (CNP) Y
G00001970 SYNGR1
synaptogyrin 1
Y (14732601) Nonsense (No) Y
G00001970 SYNGR1
synaptogyrin 1
Y (17049558) Single nucleotide polymorphism (SNP) ?
G00001970 SYNGR1
synaptogyrin 1
Y (17049558) Microinsertion (MI) ?
G00001970 SYNGR1
synaptogyrin 1
Y (17049558) Insertion (I) ?
G00000026 GRIN2A
glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Y (15774266) Repeat polymorphism (RP) Y
G00000026 GRIN2A
glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Y (12724619) Repeat polymorphism (RP) Y
G00001420 GSK3B
glycogen synthase kinase 3 beta
Y (15719395) Single nucleotide polymorphism (SNP) N
G00002531 SNAP25
synaptosomal-associated protein, 25kDa
Y (11287790) Repeat polymorphism (RP) Y
G00002531 SNAP25
synaptosomal-associated protein, 25kDa
Y (15823421) Polymorphism (P) Y
G00001806 PLP1
proteolipid protein 1
Y (15694262) Single nucleotide polymorphism (SNP) Y
G00002164 IRS1
insulin receptor substrate 1
Y (17044098) Single nucleotide polymorphism (SNP) N
G00000029 DLG4
discs, large homolog 4 (Drosophila)
Y (16530958) Polymorphism (P) N
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (12140778) Single nucleotide polymorphism (SNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (14623375) Repeat polymorphism (RP) N
G00001922 STX1A
syntaxin 1A (brain)
Y (15219469) Single nucleotide polymorphism (SNP) Y
G00001690 DPYSL2
dihydropyrimidinase-like 2
Y (16321170) Single nucleotide polymorphism (SNP) N
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (16549338) Polymorphism (P) Y
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (15841096) Single nucleotide polymorphism (SNP) ?
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (10910800) Single nucleotide polymorphism (SNP) N
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (11317224) Single nucleotide polymorphism (SNP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (8942465) Repeat polymorphism (RP) N
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (12467946) Single nucleotide polymorphism (SNP) N
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (15305151) Unknown (?) Y
G00002118 DLGAP1
discs, large (Drosophila) homolog-associated protein 1
Y (12950712) Single nucleotide polymorphism (SNP) N

References

  • Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia.

    Cheng MC and Chen CH

    Institute of Medical Sciences, Tzu-Chi University, Hualien City 970, Taiwan.

    Synaptogyrin 1 gene (SYNGR1) is considered as a positional candidate gene for schizophrenia because of its location at chromosome 22q13, a region linked to schizophrenia, and its reduced expression in postmortem brain of patients with schizophrenia. Additionally, genetic studies also reported association of SYNGR1 is with schizophrenia and bipolar disorder in southern India. Prompted by these findings, we were interested to know if SYNGR1 is also associated with schizophrenia in our population. Therefore, we systematically searched for SYNGR1 mutations in a cohort of Han Chinese patients from Taiwan. Four single nucleotide polymorphisms (SNPs) were identified, including three at the putative core promoter region (g.-673A>C, g.-377G>A and g.-318G>T) that are in strong linkage disequilibrium and one in intron 2 (IVS2-64C>G). Computer program predicts that g.-637A>C and g.318G>T may change transcription binding sites of AP-1 and TGT3, respectively. We further carried out SNP- and haplotype-based case-control association studies of these tress SNPs with schizophrenia. However, no association was detected between these SNPs and schizophrenia in our sample. Nevertheless, we identified several rare mutations in exon 6 of SYNGR1 gene in our patient cohort (n=497), including a 3-bp (AAC) in-frame insertion between codon 202 and 203 (P202_T203insN) in two patients, an A-to-G missense mutation (c.665A>G) at codon 222 (D222G) in one patient, a synonymous mutation (c.669C>T) at codon 223 (T223T) in one patient, and a C-to-T at 3' UTR of SYNGR1 (c.772C>T) in one patient. These are mutations were not found in 507 control subjects, suggesting further functional assays are warranted to verify their relevance to the pathogenesis of schizophrenia.

    Journal of psychiatric research 2007;41;12;1027-31

  • IGF1, growth pathway polymorphisms and schizophrenia: a pooling study.

    Gunnell D, Lewis S, Wilkinson J, Georgieva L, Davey GS, Day IN, Holly JM, O'Donovan MC, Owen MJ, Kirov G and Zammit S

    Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK. D.J.Gunnell@Bristol.ac.uk

    It has been hypothesized that insulin-like growth factors (IGFs) and components of the growth-hormone (GH)-IGF axis may underlie reported associations of poor fetal and childhood growth with schizophrenia. We have investigated the association of schizophrenia with 16 SNPs spanning the IGF1 gene with an inter-marker distance of approximately 2-3 kb. We also examined associations with four common functional polymorphisms of genes involved in aspects of the GH-IGF system--the IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), growth hormone (GH1), and IGF binding protein-3 (IGFBP3). The study was based on an analysis of pooled DNA samples from 648 UK and Irish cases of schizophrenia and 712 blood donor controls and of 297 Bulgarian parent offspring trios. In replicated pool analyses, none of the 16 SNPs in IGF1 nor the 4 key SNPs in the other growth pathway genes were associated with schizophrenia. SNP coverage of IGF1 was extensive, so our findings do not support a major role for IGF-I in the aetiology of schizophrenia.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;1;117-20

  • An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis.

    Zhao X, Tang R, Xiao Z, Shi Y, Feng G, Gu N, Shi J, Xing Y, Yan L, Sang H, Zhu S, Liu H, Chen W, Liu J, Tang W, Zhang J and He L

    Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.

    Several linkage studies support a susceptibility locus for schizophrenia on chromosome 8p21-22. In this study, we investigated a gene mapping to 8p21, dihydropyrimidinase-like 2 (DPYSL2). DPYSL2 plays an important role in axonal formation and dysfunction of DPYSL2 may result in neurodevelopmental abnormalities. In previous studies, the expression of the gene has been shown to display alteration in the brain of schizophrenia patients compared with those of healthy controls. Recently, Nakata and colleagues found polymorphisms in the 3'-end of DPYSL2 to be associated with schizophrenia, especially the paranoid type, in a Japanese population. In this study, we genotyped four SNPs in DPYSL2 in 2552 Chinese Han specimens. Case-control and TDT analyses were performed to detect association of DPYSL2 with schizophrenia. However, no allele, genotype or haplotype association was found. We investigated the expression of DPYSL2 in 29 schizophrenia patients and 54 healthy controls using quantitative real-time PCR and no difference was found between the two groups. In a comparative allele-specific expression test, we used two SNPs as markers. Only a small proportion of heterozygotes revealed a significant difference (>20%) in allele representation. The results indicated the mRNA level did not contribute mainly in the altered expression of the gene in schizophrenia patients. Although our results provided no evidence for DPYSL2 itself as a susceptibility gene for schizophrenia, recent findings have indicated that DPYSL2 may interact with other candidate genes for schizophrenia and be worthy of further studies.

    The international journal of neuropsychopharmacology 2006;9;6;705-12

  • N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.

    Martucci L, Wong AH, De Luca V, Likhodi O, Wong GW, King N and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, R-31, 250 College Street, Toronto (ON), Canada M5T 1R8.

    The NR2B protein is a critical structural and functional subunit of the NMDA glutamate receptor. The glutamate neurotransmitter system has been implicated in psychosis and schizophrenia, and so we looked for genetic association and measured gene expression in human DNA and brain samples, respectively, of the GRIN2B gene that codes for the NR2B protein. We tested three genetic polymorphisms: G-200T (5'UTR), A5806C and T5988C (both 3'UTR) in 180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms). We measured brain GRIN2B mRNA levels in schizophrenia, bipolar disorder and unaffected controls (n = 35 each). We detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.

    Schizophrenia research 2006;84;2-3;214-21

  • No genetic association between postsynaptic density-95 gene polymorphisms and schizophrenia.

    Kawashima R, Ohnuma T, Shibata N and Arai H

    Department of Psychiatry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. ritsukok@med.juntendo.ac.jp

    Disturbed glutamatergic neurotransmission, especially disturbed N-methyl-D-aspartate (NMDA) receptor function, has been hypothesized to be involved in the pathophysiology of schizophrenia. It may also involve abnormalities in the intracellular signaling machineries that are linked to the NMDA receptor. Postsynaptic density-95 is known to bind NMDA receptor subunits and is involved in intracellular signal transduction and synaptic plasticity. Recently, we reported that gene expression of postsynaptic density-95 was altered in schizophrenic brains compared to controls. Therefore, in this study, we examined six polymorphisms in and around the postsynaptic density-95 gene in 259 schizophrenic cases and 188 healthy controls using TaqMan technology. The results suggested that these six polymorphisms did not affect risk for schizophrenia.

    Neuroscience letters 2006;400;1-2;168-71

  • Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population.

    Washizuka S, Kametani M, Sasaki T, Tochigi M, Umekage T, Kohda K and Kato T

    Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama, Japan.

    Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11-13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, -3542G > A and -602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, -3542G > A and -602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter-individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;3;301-4

  • DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling.

    Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG and Holt RA

    Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Suite 100, 570 West 7th Avenue, Vancouver, BC, Canada V5Z 4S6.

    Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.

    Human molecular genetics 2006;15;5;743-9

  • Cytosolic PLA2 genes possibly contribute to the etiology of schizophrenia.

    Tao R, Yu Y, Zhang X, Guo Y, Shi J, Zhang X, Xie L, Liu S, Ju G, Xu Q, Shen Y and Wei J

    Jilin University Research Center for Genomic Medicine, School of Public Health, Jilin University, Changchun, China.

    The present study detected three single nucleotide polymorphisms (SNPs), BanISNP at the PLA2G4A locus, rs1648833 at the PLA2G4B locus, and rs1549637 at the PLA2G4C locus, to investigate a genetic association between the cytosolic PLA2 (cPLA2) genes and schizophrenia. A total of 240 Chinese parent-offspring trios of Han descent were recruited for the genetic analysis. The transmission disequilibrium test (TDT) showed allelic association for rs1549637 (chi(2) = 5.68, uncorrected P = 0.017), but not for BanISNP and rs1648833. The conditioning on genotype (COG) test revealed a disease association for the BanISNP-rs1648833 combination (chi(2) = 12.54, df = 3, P = 0.0057) and for the BanISNP-rs1549637 combination (chi(2) = 9.72, df = 2, P = 0.021), but the conditioning on allele (COA) test did not show such an association for the above two combinations. Neither the COA test nor the COG showed a disease association for the rs1648833-rs1549637 combination. In the combination of all three SNPs, the COG test, but not the COA test, showed a strong association (chi(2) = 22.93, df = 6, P = 0.0008). These findings suggest that these three cPLA2 genes may all be involved in contributing to the etiology of schizophrenia although their effect size appears to be relatively small.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;137B;1;56-8

  • An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray.

    Qin S, Zhao X, Pan Y, Liu J, Feng G, Fu J, Bao J, Zhang Z and He L

    Bio-X Life Science Research Center, Shanghai Jiao Tong University, Shanghai 230030, PR China.

    Dysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005.

    European journal of human genetics : EJHG 2005;13;7;807-14

  • The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

    Müller DJ, Klempan TA, De Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street R30, Toronto, Ont. M5T 1R8, Canada. daniel.mueller@charite.de

    The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

    Funded by: NIMH NIH HHS: MH MH33127, R10 MH53550

    Neuroscience letters 2005;379;2;81-9

  • Extended analyses support the association of a functional (GT)n polymorphism in the GRIN2A promoter with Japanese schizophrenia.

    Iwayama-Shigeno Y, Yamada K, Itokawa M, Toyota T, Meerabux JM, Minabe Y, Mori N, Inada T and Yoshikawa T

    Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.

    Dysfunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. In this study, we extended our analyses, by increasing the number of case-control samples to a total of 672 schizophrenics and 686 controls, and excluded potential sample stratification effects. We confirmed the significant allelic association between the repeat polymorphism and disease (P = 0.011), and as in the previous study, we observed an over-representation of longer alleles in schizophrenia. These results suggest a probable genetic effect for the GRIN2A promoter (GT)n variation on the predisposition to schizophrenia in Japanese cohorts.

    Neuroscience letters 2005;378;2;102-5

  • No association of GSK3beta gene (GSK3B) with Japanese schizophrenia.

    Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y and Ozaki N

    Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. ikeda-ma@fujita-hu.ac.jp

    Several lines of evidence indicate that glycogen synthase kinase-3beta (GSK3beta) is one of the candidates for schizophrenia-susceptibility factor. However, it has not been reported the association analysis between GSK3beta gene (GSK3B) and Japanese schizophrenia based on linkage disequilibrium (LD). We provide an association analysis using relatively large samples (381 schizophrenia, and 352 controls) after determination of "tag single nucleotide polymorphisms (SNPs)." In this LD mapping, we selected and genotyped for eight polymorphisms (seven SNPs and one diallelic (CAA)(n) repeat), which covered the entire region of GSK3B, and determined two "tag SNPs." In the following association analysis using these two "tag SNPs," we could not find association with Japanese schizophrenia. Furthermore, we also include subgroup analysis considering age-at-onset and subtypes, neither could we find associations. Because our samples provided quite high power, these results indicate that GSK3B may not play a major role in Japanese schizophrenia.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;134B;1;90-2

  • A family-based association study of PLP1 and schizophrenia.

    Qin W, Gao J, Xing Q, Yang J, Qian X, Li X, Guo Z, Chen H, Wang L, Huang X, Gu N, Feng G and He L

    Bio-X Life Science Research Center, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.

    Recently, proteolipid protein 1 (PLP1) has been identified as downregulated in schizophrenia by quantitative PCR and other technologies. In this work we attempted to investigate the role of PLP1 in the etiology of schizophrenia using a family based association study in 487 Chinese Han family trios. The TDT for allelic association demonstrated that, in male, a weak association was detected in SNP rs475827 with p=0.0294, suggesting that the genetic polymorphisms within PLP1 in male are likely to confer an increased susceptibility to schizophrenia in the Chinese population.

    Neuroscience letters 2005;375;3;207-10

  • Allelic association analysis of phospholipase A2 genes with schizophrenia.

    Junqueira R, Cordeiro Q, Meira-Lima I, Gattaz WF and Vallada H

    Laboratory of Neuroscience, LIM 27, Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.

    Several studies suggest increased activity of phospholipase A2 in schizophrenic patients. In the present study, variants of four genes coding for phospholipase A2 enzyme groups (sPLA2, cPLA2, iPLA2 and PAFAH) were analysed in a case-control sample using 240 schizophrenic patients and 312 healthy controls. No difference was observed on the allelic and genotypic distribution of cPLA2 and sPLA2 gene polymorphisms among the groups. The PAFAH variant was very rare in our population and therefore not informative. A significant allelic (chi2=5.86, P=0.0085, odds ratio=1.38, 95% confidence interval, 1.08-1.77) and genotypic (chi2=5.4, P=0.02) association with the iPLA2 gene polymorphism was found. In conclusion, our data suggested that iPLA2 may play a role as a susceptibility gene for schizophrenia in our sample; however, confirmatory studies in independent samples are needed.

    Psychiatric genetics 2004;14;3;157-60

  • Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia.

    Bah J, Quach H, Ebstein RP, Segman RH, Melke J, Jamain S, Rietschel M, Modai I, Kanas K, Karni O, Lerer B, Gourion D, Krebs MO, Etain B, Schürhoff F, Szöke A, Leboyer M and Bourgeron T

    Human Genetics and Cognitive Functions, Universite Paris 7, Institut Pasteur, 25, rue du docteur Roux, 75724 Paris Cedex 15, France.

    Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.

    Neuroreport 2004;15;12;1987-91

  • Association between schizophrenia and the syntaxin 1A gene.

    Wong AH, Trakalo J, Likhodi O, Yusuf M, Macedo A, Azevedo MH, Klempan T, Pato MT, Honer WG, Pato CN, Van Tol HH and Kennedy JL

    Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

    Background: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia.

    Methods: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families.

    Results: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2) = 5.898; df = 1; p =.015, family-based association test [FBAT] z = 2.280, p =.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z(c) = 2.859; p =.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP.

    Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.

    Biological psychiatry 2004;56;1;24-9

  • BanI polymorphism of the cytosolic phospholipase A2 gene may confer susceptibility to the development of schizophrenia.

    Pae CU, Yu HS, Lee KU, Kim JJ, Lee CU, Lee SJ, Jun TY, Lee C and Paik IH

    Department of Psychiatry, Kangnam St. Mary' Hospital, The Catholic University of Korea College of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, South Korea.

    Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of schizophrenia. Cytosolic phospholipase A2 (cPLA2) plays a major role in the metabolism of fatty acids but is also found in abnormalities in patients with schizophrenia. This study examined the association between the cPLA2 gene BanI polymorphism and schizophrenia. Ninety-seven Korean schizophrenia patients and 117 healthy controls participated in this study. Genotyping was performed by using polymerase chain reaction (PCR)-based methods. Genotype and allele distributions were significantly different between the schizophrenia patients and controls. In particular, the A2 allele was associated with an increased risk of schizophrenia (p = 0.003; odds ratio (OR) = 1.799; confidence interval (CI) = 1.192-2.716). However, the polymorphism was not different when the patient group was subdivided by the presence or absence of family history and by positive and negative subgroups according to the positive and negative syndrome scale (PANSS) score on schizophrenia. The results of this study replicated those of previous findings from Western countries and indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to schizophrenia.

    Progress in neuro-psychopharmacology & biological psychiatry 2004;28;4;739-41

  • A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia.

    Verma R, Chauhan C, Saleem Q, Gandhi C, Jain S and Brahmachari SK

    Functional Genomics Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi University Campus, Delhi, India.

    Background: Chromosome 22q is one of the important regions repeatedly being implicated in schizophrenia. In this region, our group previously reported an association of a CAG repeat marker (22CH3) with schizophrenia in the Indian population. Because Synaptogyrin 1 (SYNGR1), associated with presynaptic vesicles in neuronal cells, lies within 1 million base pairs of this marker, it is a potential candidate gene for schizophrenia.

    Methods: We sequenced all six exons and flanking splice junctions of the SYNGR1 gene. We also carried out reverse transcriptase polymerase chain reaction and Northern blot analysis for exon 2 containing transcript of the SYNGR1 gene.

    Results: We found a novel nonsense mutation (Trp27Ter) in exon 2 of the SYNGR1 gene in a family multiply affected with schizophrenia. Reverse transcriptase polymerase chain reaction and Northern blot analyses revealed that exon 2 containing transcript of this gene is expressed in the brain.

    Conclusions: Because the SYNGR1 gene is involved in presynaptic pathways, reduced levels of this protein might play some role in the pathogenesis of schizophrenia.

    Biological psychiatry 2004;55;2;196-9

  • Association analysis for the CA repeat polymorphism of the neuronal nitric oxide synthase (NOS1) gene and schizophrenia.

    Liou YJ, Tsai SJ, Hong CJ and Liao DL

    Schizophrenia research 2003;65;1;57-9

  • Mutation and association analysis of the DAP-1 gene with schizophrenia.

    Aoyama S, Shirakawa O, Ono H, Hashimoto T, Kajimoto Y and Maeda K

    Department of Environmental Health and Safety, Kobe University Graduate School of Medicine, Kobe, Japan.

    Glutamate dysfunction has been hypothesized to be involved in the pathophysiology of schizophrenia. The human homolog of Drosophila discs large protein (hDLG) and post-synaptic density-95-associated protein-1 (DAP-1) is one of the major proteins that are involved in intracellular signal transduction via N-methyl-d-aspartate receptors. In the present study 33 Japanese patients with schizophrenia were screened for mutations in the DAP-1 gene. A single nucleotide polymorphism was identified in the DAP-1 gene (1618A/G). A case-control study using a larger sample of unrelated patients and controls did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the DAP-1 gene is involved in vulnerability to schizophrenia.

    Psychiatry and clinical neurosciences 2003;57;5;545-7

  • Mutation screening of the Homer gene family and association analysis in schizophrenia.

    Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.

    Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;120B;1;18-21

  • N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses.

    Martucci L, Wong AH, Trakalo J, Cate-Carter T, Wong GW, Macciardi FM and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, Toronto, Ontario, Canada.

    The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;119B;1;24-7

  • A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia.

    Itokawa M, Yamada K, Yoshitsugu K, Toyota T, Suga T, Ohba H, Watanabe A, Hattori E, Shimizu H, Kumakura T, Ebihara M, Meerabux JM, Toru M and Yoshikawa T

    Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.

    Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene. A case-control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P = 0.05, Mann-Whitney test), with longer alleles overly represented in patients. An in-vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)(n) repeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P = 0.01, Spearman's Rank test). These results illustrate a genotype-phenotype correlation in schizophrenia and suggest that the longer (GT)(n) stretch may act as a risk-conferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.

    Pharmacogenetics 2003;13;5;271-8

  • Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia.

    Begni S, Moraschi S, Bignotti S, Fumagalli F, Rillosi L, Perez J and Gennarelli M

    Genetics Unit, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy

    Background: The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study.

    Methods: The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease.

    Results: We found that the C allele may alter a consensus sequence for the transcription factor NF-kappa B and that its frequency was higher in patients than in control subjects (p =.0085). The genotype distribution also was different, with p =.034 (if C allele dominant, p =.0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076).

    Conclusions: The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia.

    Biological psychiatry 2003;53;7;617-9

  • Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia.

    Shibata H, Shibata A, Ninomiya H, Tashiro N and Fukumaki Y

    Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

    The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21, a schizophrenia susceptibility region, as suggested by multiple linkage studies. We examined 15 SNPs evenly distributed in the entire GRIK2 region (>700 kb) in Japanese patients with schizophrenia (n=100) and controls (n=100). Neither genotype nor allele frequency showed a significant association with the disorder. We constructed 2-SNP haplotypes from the 15 SNPs. Although we observed three long linkage disequilibrium blocks (>150 kb) within the GRIK2 region, none of the pairwise haplotypes showed a significant association with the disorder. Therefore, we conclude that GRIK2 does not play a major role in the pathogenesis of schizophrenia in the Japanese population.

    Psychiatry research 2002;113;1-2;59-67

  • Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients.

    Hung CC, Chen HY and Chen CH

    Institute of Human Genetics, Tzu-Chi University, Hualien City, Taiwan. cchen@mail.tcu.edu.tw

    Schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population.

    Psychiatric genetics 2002;12;4;225-30

  • Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia.

    Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N and Fukumaki Y

    Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.

    Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.

    Schizophrenia research 2002;58;1;83-6

  • Alteration of branch site consensus sequence and enhanced pre-mRNA splicing of an NMDAR1 intron not associated with schizophrenia.

    Hammond L, Castanotto D, Rice SR, Nimgaonkar VL, Wirshing DA, Rossi JJ, Heston LL and Sobell JL

    Division of Molecular Medicine, City of Hope National Medical Center, Duarte, California 91010-0269, USA.

    Aberrant splicing of pre-mRNA is recognized to account for a significant minority of disease-causing mutations. The N-methyl-D-aspartate receptor (NMDA) subunit gene R1 (NMDAR1) is alternatively spliced to produce eight length variants. In an examination of the NMDAR1 as a candidate gene in schizophrenia, a presumed microdeletion/insertion (del/ins) was observed in intron 10 of an African-American male near a weak putative branch-site consensus sequence. Although exon 10 is not known to be alternatively spliced, the del/ins was posited to alter splicing efficiency. If splicing were abolished and intron retention occurred, an in-frame translation product of more than 250 amino acids was predicted. To explore splicing efficiency, mini genes were examined through primer-extension analyses in NIH293 embryonic kidney cell cultures. Rather than disruption of splicing, the del/ins allele exhibited a fivefold enhancement in splicing. In an association analysis with additional schizophrenic cases and unaffected controls, all of African-American descent, the mutant allele was observed at equivalent frequencies. A family study also did not support cosegregation of the variant allele with psychiatric disease.

    American journal of medical genetics 2002;114;6;631-6

  • Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia.

    Shinkai T, Ohmori O, Hori H and Nakamura J

    Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.

    Nitric oxide (NO) has been identified as a widespread and multifunctional biological messenger molecule in the central nervous system (CNS), with possible roles in neurotransmission, neurosecretion, synaptic plasticity, and tissue injury in many neurological disorders, including schizophrenia. Neuronal NO is widely produced in the brain from L-arginine catalyzed by neuronal NO synthase (NOS1). We therefore hypothesized that the NOS1 gene may play a role in the pathophysiology of schizophrenia. In the present study, we examined the genetic association between a novel single nucleotide polymorphism (SNP: a C-->T transition located 276 base pairs downstream from the translation termination site) of the human NOS1 gene, which is located in chromosome 12q24, and schizophrenia (215 Japanese patients with schizophrenia and 182 healthy controls). The allele frequencies of the polymorphism in exon 29 of the NOS1 gene differed significantly between patients with schizophrenia and controls (chi(2) = 20.10, df = 1, P = 0.000007; relative risk = 1.92; 95% confidence interval = 1.44-2.55). Our results suggest that the NOS1 gene polymorphism may confer increased susceptibility to schizophrenia.

    Molecular psychiatry 2002;7;6;560-3

  • Association studies of cytosolic phospholipase A2 polymorphisms and schizophrenia among two independent family-based samples.

    Chowdari KV, Brandstaetter B, Semwal P, Bhatia T, Deshpande S, Reddy R, Wood J, Weinberg CR, Thelma BK and Nimgaonkar VL

    Department of Psychiatry, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

    An association between the cytosolic phospholipase A2 locus (cPLA2) and schizophrenia has been reported using two polymorphic DNA markers. In an attempt to replicate these results, two independent family-based samples were ascertained from the United States and India (86 and 159 families, respectively). No significant associations were detected in either sample.

    Funded by: FIC NIH HHS: R03 TW00730; NIMH NIH HHS: MH01489, MH53459, MH56242, R01 MH056242, R10 MH056242

    Psychiatric genetics 2001;11;4;207-12

  • The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia.

    Devon RS, Anderson S, Teague PW, Muir WJ, Murray V, Pelosi AJ, Blackwood DH and Porteous DJ

    Medical Genetics Section, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

    The G-protein coupled metabotropic glutamate receptors (GRMs/mGluRs) have been implicated in the aetiology of schizophrenia as they modulate the NMDA response and that of other neurotransmitters including dopamine and GABA.(1-3) Electrophysiological studies in GRM subtype 5 knockout mice reveal, in one study, a sensorimotor gating deficit characteristic of schizophrenia and in another, a key rôle for this gene in the modulation of hippocampal NMDA-dependent synaptic plasticity. In humans, GRM5 levels are increased in certain pyramidal cell neurons in schizophrenics vs controls.(6) Finally, GRM5 has been mapped to 11q14, neighbouring a translocation that segregates with schizophrenia and related psychoses in a large Scottish family, F23 (MLOD score 6.0). We determined the intron/exon structure of GRM5 and identified a novel intragenic microsatellite. A case-control association study identified a significant difference in allele frequency distribution between schizophrenics and controls (P = 0.04). This is suggestive of involvement of the GRM5 gene in schizophrenia in this population.

    Molecular psychiatry 2001;6;3;311-4

  • Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients.

    Rice SR, Niu N, Berman DB, Heston LL and Sobell JL

    Division of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USA.

    Glutamatergic dysregulation has been hypothesized to play a role in schizophrenia. The N-methyl-D-aspartate (NMDA) type of glutamate receptor especially is of interest because, in addition to binding sites for glutamate and glycine, a necessary co-agonist, this receptor also contains noncompetitive binding sites for the psychotomimetics phencyclidine (PCP), MK-801, and ketamine. PCP-induced psychosis has been a useful disease model in that both the positive as well as the negative symptomatologies seen in schizophrenia are observed. Recently, a mouse deficient in expression of the NR1 subunit gene (NMDAR1) of the heteromeric receptor has been developed and shown to display aberrant behaviors, with reduced social and sexual interactions as well as increased stereotypic motor activity. In an extensive examination of the NMDAR1 gene in our laboratory in approximately 100 chronic schizophrenic patients, 28 unique sequence changes were identified, including eight single nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'UTR), six SNPs in coding regions (cSNPs), eleven intronic SNPs, two intronic deletions of 7 and 30 bp, and an intronic microinsertion/deletion. With the exception of one previously reported cSNP, all of the identified changes were novel. The frequency of polymorphisms differed significantly by ethnicity and several appeared to be in linkage disequilibrium. None of the changes appeared likely to be of functional significance, thus suggesting that changes in the genomic NMDAR1 are unlikely to contribute to the etiology of schizophrenia. Estimates of nucleotide diversity are comparable to those observed in studies of other genes.

    Funded by: NIMH NIH HHS: MH54232

    Molecular psychiatry 2001;6;3;274-84

  • Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2.

    Frieboes RM, Moises HW, Gattaz WF, Yang L, Li T, Liu X, Vetter P, Macciardi F, Hwu HG and Henn F

    Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Kiel, Germany.

    The well-established role of genetic factors in the etiology of schizophrenia together with reports of allelic association with cPLA2, a phospholipase-A(2) gene, a reported increase of phospholipase-A(2) activity, and the phospholipase-A(2) hypothesis of Horrobin et al. [1995: Med Hypotheses 45:605-613] strongly support cPLA2 (PLA2G4A) and sPLA2 (PLA2G1B) as candidate genes for schizophrenia. In search for allelic association between these phospholipase-A(2) genes and schizophrenia, two samples of Chinese and European origins, in total 328 unrelated schizophrenic patients and their parents, were investigated using Falk and Rubinstein's haplotype relative risk method. Both genes showed marginally significant evidence for association in the total sample (P <or= 0.05), which, however, did not survive the Bonferroni correction for multiple testing. In conclusion, our results do not provide support for the phospholipase-A(2) hypothesis of schizophrenia. Additional studies will be necessary to rule out a possible confounding effect of niacin sensitivity as postulated by Hudson et al. [1999: Biol Psychiatr 46:401-405].

    American journal of medical genetics 2001;105;3;246-9

  • Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.

    Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K and Arinami T

    Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, 305-8575, Ibaraki, Japan.

    NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted.

    Molecular psychiatry 2001;6;2;211-6

  • An association study between polymorphism of L1CAM gene and schizophrenia in a Japanese sample.

    Kurumaji A, Nomoto H, Okano T and Toru M

    Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Japan. 0724.psyc@med.tmd.ac.jp

    L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

    American journal of medical genetics 2001;105;1;99-104

  • Polymorphism of the 5'-upstream region of the human SNAP-25 gene: an association analysis with schizophrenia.

    Tachikawa H, Harada S, Kawanishi Y, Okubo T and Suzuki T

    Department of Psychiatry, Kurita Hospital, Ibaraki, Japan. mg8@ea.mbn.or.jp

    Recent studies have suggested that synaptic abnormalities may be part of the pathophysiology of schizophrenia. SNAP-25 (synaptosomal-associated protein of 25 kD) is one of the synaptic proteins responsible for presynaptic neurotransmission, axonal elongation and synaptogenesis. Genetic variation in the 5'-upstream region of the SNAP-25 gene was analyzed in 87 unrelated schizophrenic patients and 100 healthy controls. A novel polymorphic (TAAA)(n) tandem repeat was identified in the 5'-upstream region. There were no significant differences between the patient and the control groups in the distribution of repeat numbers of alleles or genotypes. In addition, no associations were found between the polymorphism for subtypes, longitudinal courses or positive family history of the patients. Our results suggest that polymorphisms in the 5'-upstream region of the SNAP-25 gene have no association with schizophrenia.

    Neuropsychobiology 2001;43;3;131-3

  • Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia.

    Sakurai K, Toru M, Yamakawa-Kobayashi K and Arinami T

    Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, 305-8575, Ibaraki-ken, Japan.

    Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.

    Neuroscience letters 2000;296;2-3;168-70

  • Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia.

    Nishiguchi N, Shirakawa O, Ono H, Hashimoto T and Maeda K

    Department of Psychiatry and Neurology, Kobe University School of Medicine, Japan.

    Objective: N-methyl-D-aspartate (NMDA) receptor antagonists are known to produce a syndrome resembling schizophrenia, probably due to their blockade of NMDA receptors. The NMDA receptor 2B (NR2B) subunit has been identified as one of the major proteins in the postsynaptic density at glutamatergic synapses, suggesting that the carboxyl-terminal domain of the NR2B subunit may play a significant role in intracellular signal transduction.

    Method: The authors screened for genetic variations in the region of the NR2B subunit gene encoding the carboxyl-terminal intracellular domain in patients with schizophrenia and studied the association between schizophrenia and a novel polymorphism of the NR2B subunit gene.

    Results: One silent mutation (2664C/T) was identified. No significant differences in the frequencies of 2664C/T genotypes and alleles were found between patients with schizophrenia and healthy comparison subjects.

    Conclusions: The findings provided no evidence of an association between schizophrenia and the 2664C/T polymorphism of the NR2B subunit gene.

    The American journal of psychiatry 2000;157;8;1329-31

  • Association of the Ban I dimorphic site at the human cytosolic phospholipase A2 gene with schizophrenia.

    Peet M, Ramchand CN, Lee J, Telang SD, Vankar GK, Shah S and Wei J

    University Department of Psychiatry, Northern General Hospital, Sheffield, UK. m.peet@sheffield.ac.uk

    There is evidence of increased phospholipid breakdown in cell membranes of patients suffering from schizophrenia. This may be related to increased levels of the enzyme cytosolic phospholipase A2 (cPLA2) which have been reported in schizophrenic subjects. We have identified a Ban I dimorphic site on the first intron of the cPLA2 gene. Schizophrenic subjects were found to have a significant excess of the A2/A2 homozygote relative to healthy control subjects. Genetically determined alterations in phospholipase activity may thus underlie the reported abnormalities of phospholipid metabolism in schizophrenia.

    Psychiatric genetics 1998;8;3;191-2

  • Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia.

    Chen AC, Kalsi G, Brynjolfsson J, Sigmundsson T, Curtis D, Butler R, Read T, Murphy P, Petursson H, Barnard EA and Gurling HM

    Department of Psychiatry, University College London Medical School, U.K.

    Objective: Previous research has consistently implicated genetic factors in the pathogenesis of schizophrenia. It has been hypothesized that an abnormality in glutamatergic function is of etiologic importance in schizophrenia, and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis the authors sought to detect linkage between the GluR6 glutamate receptor gene and schizophrenia.

    Method: Twenty-three English and Icelandic families containing multiple cases of schizophrenia were genotyped with a microsatellite trinucleotide repeat polymorphism localized at the GluR6 glutamate receptor locus. Lod scores, model-free linkage analysis, and extended relative pair analysis were used to test for linkage.

    Results: No statistically significant evidence of linkage between GluR6 and schizophrenia was found.

    Conclusions: The results do not support the hypothesis that GluR6 allelic variants provide a major gene contribution to the etiology of schizophrenia in a large proportion of these pedigrees.

    Funded by: Wellcome Trust

    The American journal of psychiatry 1996;153;12;1634-6

Literature (40)

Pubmed - human_disease

  • Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia.

    Cheng MC and Chen CH

    Institute of Medical Sciences, Tzu-Chi University, Hualien City 970, Taiwan.

    Synaptogyrin 1 gene (SYNGR1) is considered as a positional candidate gene for schizophrenia because of its location at chromosome 22q13, a region linked to schizophrenia, and its reduced expression in postmortem brain of patients with schizophrenia. Additionally, genetic studies also reported association of SYNGR1 is with schizophrenia and bipolar disorder in southern India. Prompted by these findings, we were interested to know if SYNGR1 is also associated with schizophrenia in our population. Therefore, we systematically searched for SYNGR1 mutations in a cohort of Han Chinese patients from Taiwan. Four single nucleotide polymorphisms (SNPs) were identified, including three at the putative core promoter region (g.-673A>C, g.-377G>A and g.-318G>T) that are in strong linkage disequilibrium and one in intron 2 (IVS2-64C>G). Computer program predicts that g.-637A>C and g.318G>T may change transcription binding sites of AP-1 and TGT3, respectively. We further carried out SNP- and haplotype-based case-control association studies of these tress SNPs with schizophrenia. However, no association was detected between these SNPs and schizophrenia in our sample. Nevertheless, we identified several rare mutations in exon 6 of SYNGR1 gene in our patient cohort (n=497), including a 3-bp (AAC) in-frame insertion between codon 202 and 203 (P202_T203insN) in two patients, an A-to-G missense mutation (c.665A>G) at codon 222 (D222G) in one patient, a synonymous mutation (c.669C>T) at codon 223 (T223T) in one patient, and a C-to-T at 3' UTR of SYNGR1 (c.772C>T) in one patient. These are mutations were not found in 507 control subjects, suggesting further functional assays are warranted to verify their relevance to the pathogenesis of schizophrenia.

    Journal of psychiatric research 2007;41;12;1027-31

  • IGF1, growth pathway polymorphisms and schizophrenia: a pooling study.

    Gunnell D, Lewis S, Wilkinson J, Georgieva L, Davey GS, Day IN, Holly JM, O'Donovan MC, Owen MJ, Kirov G and Zammit S

    Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK. D.J.Gunnell@Bristol.ac.uk

    It has been hypothesized that insulin-like growth factors (IGFs) and components of the growth-hormone (GH)-IGF axis may underlie reported associations of poor fetal and childhood growth with schizophrenia. We have investigated the association of schizophrenia with 16 SNPs spanning the IGF1 gene with an inter-marker distance of approximately 2-3 kb. We also examined associations with four common functional polymorphisms of genes involved in aspects of the GH-IGF system--the IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), growth hormone (GH1), and IGF binding protein-3 (IGFBP3). The study was based on an analysis of pooled DNA samples from 648 UK and Irish cases of schizophrenia and 712 blood donor controls and of 297 Bulgarian parent offspring trios. In replicated pool analyses, none of the 16 SNPs in IGF1 nor the 4 key SNPs in the other growth pathway genes were associated with schizophrenia. SNP coverage of IGF1 was extensive, so our findings do not support a major role for IGF-I in the aetiology of schizophrenia.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;1;117-20

  • An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis.

    Zhao X, Tang R, Xiao Z, Shi Y, Feng G, Gu N, Shi J, Xing Y, Yan L, Sang H, Zhu S, Liu H, Chen W, Liu J, Tang W, Zhang J and He L

    Bio-X Center, Shanghai Jiao Tong University, Shanghai, China.

    Several linkage studies support a susceptibility locus for schizophrenia on chromosome 8p21-22. In this study, we investigated a gene mapping to 8p21, dihydropyrimidinase-like 2 (DPYSL2). DPYSL2 plays an important role in axonal formation and dysfunction of DPYSL2 may result in neurodevelopmental abnormalities. In previous studies, the expression of the gene has been shown to display alteration in the brain of schizophrenia patients compared with those of healthy controls. Recently, Nakata and colleagues found polymorphisms in the 3'-end of DPYSL2 to be associated with schizophrenia, especially the paranoid type, in a Japanese population. In this study, we genotyped four SNPs in DPYSL2 in 2552 Chinese Han specimens. Case-control and TDT analyses were performed to detect association of DPYSL2 with schizophrenia. However, no allele, genotype or haplotype association was found. We investigated the expression of DPYSL2 in 29 schizophrenia patients and 54 healthy controls using quantitative real-time PCR and no difference was found between the two groups. In a comparative allele-specific expression test, we used two SNPs as markers. Only a small proportion of heterozygotes revealed a significant difference (>20%) in allele representation. The results indicated the mRNA level did not contribute mainly in the altered expression of the gene in schizophrenia patients. Although our results provided no evidence for DPYSL2 itself as a susceptibility gene for schizophrenia, recent findings have indicated that DPYSL2 may interact with other candidate genes for schizophrenia and be worthy of further studies.

    The international journal of neuropsychopharmacology 2006;9;6;705-12

  • No genetic association between postsynaptic density-95 gene polymorphisms and schizophrenia.

    Kawashima R, Ohnuma T, Shibata N and Arai H

    Department of Psychiatry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. ritsukok@med.juntendo.ac.jp

    Disturbed glutamatergic neurotransmission, especially disturbed N-methyl-D-aspartate (NMDA) receptor function, has been hypothesized to be involved in the pathophysiology of schizophrenia. It may also involve abnormalities in the intracellular signaling machineries that are linked to the NMDA receptor. Postsynaptic density-95 is known to bind NMDA receptor subunits and is involved in intracellular signal transduction and synaptic plasticity. Recently, we reported that gene expression of postsynaptic density-95 was altered in schizophrenic brains compared to controls. Therefore, in this study, we examined six polymorphisms in and around the postsynaptic density-95 gene in 259 schizophrenic cases and 188 healthy controls using TaqMan technology. The results suggested that these six polymorphisms did not affect risk for schizophrenia.

    Neuroscience letters 2006;400;1-2;168-71

  • DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling.

    Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG and Holt RA

    Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Suite 100, 570 West 7th Avenue, Vancouver, BC, Canada V5Z 4S6.

    Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.

    Human molecular genetics 2006;15;5;743-9

  • Cytosolic PLA2 genes possibly contribute to the etiology of schizophrenia.

    Tao R, Yu Y, Zhang X, Guo Y, Shi J, Zhang X, Xie L, Liu S, Ju G, Xu Q, Shen Y and Wei J

    Jilin University Research Center for Genomic Medicine, School of Public Health, Jilin University, Changchun, China.

    The present study detected three single nucleotide polymorphisms (SNPs), BanISNP at the PLA2G4A locus, rs1648833 at the PLA2G4B locus, and rs1549637 at the PLA2G4C locus, to investigate a genetic association between the cytosolic PLA2 (cPLA2) genes and schizophrenia. A total of 240 Chinese parent-offspring trios of Han descent were recruited for the genetic analysis. The transmission disequilibrium test (TDT) showed allelic association for rs1549637 (chi(2) = 5.68, uncorrected P = 0.017), but not for BanISNP and rs1648833. The conditioning on genotype (COG) test revealed a disease association for the BanISNP-rs1648833 combination (chi(2) = 12.54, df = 3, P = 0.0057) and for the BanISNP-rs1549637 combination (chi(2) = 9.72, df = 2, P = 0.021), but the conditioning on allele (COA) test did not show such an association for the above two combinations. Neither the COA test nor the COG showed a disease association for the rs1648833-rs1549637 combination. In the combination of all three SNPs, the COG test, but not the COA test, showed a strong association (chi(2) = 22.93, df = 6, P = 0.0008). These findings suggest that these three cPLA2 genes may all be involved in contributing to the etiology of schizophrenia although their effect size appears to be relatively small.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;137B;1;56-8

  • The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

    Müller DJ, Klempan TA, De Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Street R30, Toronto, Ont. M5T 1R8, Canada. daniel.mueller@charite.de

    The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

    Funded by: NIMH NIH HHS: MH MH33127, R10 MH53550

    Neuroscience letters 2005;379;2;81-9

  • Allelic association analysis of phospholipase A2 genes with schizophrenia.

    Junqueira R, Cordeiro Q, Meira-Lima I, Gattaz WF and Vallada H

    Laboratory of Neuroscience, LIM 27, Institute of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.

    Several studies suggest increased activity of phospholipase A2 in schizophrenic patients. In the present study, variants of four genes coding for phospholipase A2 enzyme groups (sPLA2, cPLA2, iPLA2 and PAFAH) were analysed in a case-control sample using 240 schizophrenic patients and 312 healthy controls. No difference was observed on the allelic and genotypic distribution of cPLA2 and sPLA2 gene polymorphisms among the groups. The PAFAH variant was very rare in our population and therefore not informative. A significant allelic (chi2=5.86, P=0.0085, odds ratio=1.38, 95% confidence interval, 1.08-1.77) and genotypic (chi2=5.4, P=0.02) association with the iPLA2 gene polymorphism was found. In conclusion, our data suggested that iPLA2 may play a role as a susceptibility gene for schizophrenia in our sample; however, confirmatory studies in independent samples are needed.

    Psychiatric genetics 2004;14;3;157-60

  • BanI polymorphism of the cytosolic phospholipase A2 gene may confer susceptibility to the development of schizophrenia.

    Pae CU, Yu HS, Lee KU, Kim JJ, Lee CU, Lee SJ, Jun TY, Lee C and Paik IH

    Department of Psychiatry, Kangnam St. Mary' Hospital, The Catholic University of Korea College of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, South Korea.

    Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of schizophrenia. Cytosolic phospholipase A2 (cPLA2) plays a major role in the metabolism of fatty acids but is also found in abnormalities in patients with schizophrenia. This study examined the association between the cPLA2 gene BanI polymorphism and schizophrenia. Ninety-seven Korean schizophrenia patients and 117 healthy controls participated in this study. Genotyping was performed by using polymerase chain reaction (PCR)-based methods. Genotype and allele distributions were significantly different between the schizophrenia patients and controls. In particular, the A2 allele was associated with an increased risk of schizophrenia (p = 0.003; odds ratio (OR) = 1.799; confidence interval (CI) = 1.192-2.716). However, the polymorphism was not different when the patient group was subdivided by the presence or absence of family history and by positive and negative subgroups according to the positive and negative syndrome scale (PANSS) score on schizophrenia. The results of this study replicated those of previous findings from Western countries and indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to schizophrenia.

    Progress in neuro-psychopharmacology & biological psychiatry 2004;28;4;739-41

  • Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia.

    Begni S, Moraschi S, Bignotti S, Fumagalli F, Rillosi L, Perez J and Gennarelli M

    Genetics Unit, IRCCS S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy

    Background: The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study.

    Methods: The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease.

    Results: We found that the C allele may alter a consensus sequence for the transcription factor NF-kappa B and that its frequency was higher in patients than in control subjects (p =.0085). The genotype distribution also was different, with p =.034 (if C allele dominant, p =.0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076).

    Conclusions: The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia.

    Biological psychiatry 2003;53;7;617-9

  • Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia.

    Shibata H, Shibata A, Ninomiya H, Tashiro N and Fukumaki Y

    Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

    The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21, a schizophrenia susceptibility region, as suggested by multiple linkage studies. We examined 15 SNPs evenly distributed in the entire GRIK2 region (>700 kb) in Japanese patients with schizophrenia (n=100) and controls (n=100). Neither genotype nor allele frequency showed a significant association with the disorder. We constructed 2-SNP haplotypes from the 15 SNPs. Although we observed three long linkage disequilibrium blocks (>150 kb) within the GRIK2 region, none of the pairwise haplotypes showed a significant association with the disorder. Therefore, we conclude that GRIK2 does not play a major role in the pathogenesis of schizophrenia in the Japanese population.

    Psychiatry research 2002;113;1-2;59-67

  • Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia.

    Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N and Fukumaki Y

    Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.

    Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.

    Schizophrenia research 2002;58;1;83-6

  • Association studies of cytosolic phospholipase A2 polymorphisms and schizophrenia among two independent family-based samples.

    Chowdari KV, Brandstaetter B, Semwal P, Bhatia T, Deshpande S, Reddy R, Wood J, Weinberg CR, Thelma BK and Nimgaonkar VL

    Department of Psychiatry, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

    An association between the cytosolic phospholipase A2 locus (cPLA2) and schizophrenia has been reported using two polymorphic DNA markers. In an attempt to replicate these results, two independent family-based samples were ascertained from the United States and India (86 and 159 families, respectively). No significant associations were detected in either sample.

    Funded by: FIC NIH HHS: R03 TW00730; NIMH NIH HHS: MH01489, MH53459, MH56242, R01 MH056242, R10 MH056242

    Psychiatric genetics 2001;11;4;207-12

  • The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia.

    Devon RS, Anderson S, Teague PW, Muir WJ, Murray V, Pelosi AJ, Blackwood DH and Porteous DJ

    Medical Genetics Section, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

    The G-protein coupled metabotropic glutamate receptors (GRMs/mGluRs) have been implicated in the aetiology of schizophrenia as they modulate the NMDA response and that of other neurotransmitters including dopamine and GABA.(1-3) Electrophysiological studies in GRM subtype 5 knockout mice reveal, in one study, a sensorimotor gating deficit characteristic of schizophrenia and in another, a key rôle for this gene in the modulation of hippocampal NMDA-dependent synaptic plasticity. In humans, GRM5 levels are increased in certain pyramidal cell neurons in schizophrenics vs controls.(6) Finally, GRM5 has been mapped to 11q14, neighbouring a translocation that segregates with schizophrenia and related psychoses in a large Scottish family, F23 (MLOD score 6.0). We determined the intron/exon structure of GRM5 and identified a novel intragenic microsatellite. A case-control association study identified a significant difference in allele frequency distribution between schizophrenics and controls (P = 0.04). This is suggestive of involvement of the GRM5 gene in schizophrenia in this population.

    Molecular psychiatry 2001;6;3;311-4

  • Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients.

    Rice SR, Niu N, Berman DB, Heston LL and Sobell JL

    Division of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USA.

    Glutamatergic dysregulation has been hypothesized to play a role in schizophrenia. The N-methyl-D-aspartate (NMDA) type of glutamate receptor especially is of interest because, in addition to binding sites for glutamate and glycine, a necessary co-agonist, this receptor also contains noncompetitive binding sites for the psychotomimetics phencyclidine (PCP), MK-801, and ketamine. PCP-induced psychosis has been a useful disease model in that both the positive as well as the negative symptomatologies seen in schizophrenia are observed. Recently, a mouse deficient in expression of the NR1 subunit gene (NMDAR1) of the heteromeric receptor has been developed and shown to display aberrant behaviors, with reduced social and sexual interactions as well as increased stereotypic motor activity. In an extensive examination of the NMDAR1 gene in our laboratory in approximately 100 chronic schizophrenic patients, 28 unique sequence changes were identified, including eight single nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'UTR), six SNPs in coding regions (cSNPs), eleven intronic SNPs, two intronic deletions of 7 and 30 bp, and an intronic microinsertion/deletion. With the exception of one previously reported cSNP, all of the identified changes were novel. The frequency of polymorphisms differed significantly by ethnicity and several appeared to be in linkage disequilibrium. None of the changes appeared likely to be of functional significance, thus suggesting that changes in the genomic NMDAR1 are unlikely to contribute to the etiology of schizophrenia. Estimates of nucleotide diversity are comparable to those observed in studies of other genes.

    Funded by: NIMH NIH HHS: MH54232

    Molecular psychiatry 2001;6;3;274-84

  • Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2.

    Frieboes RM, Moises HW, Gattaz WF, Yang L, Li T, Liu X, Vetter P, Macciardi F, Hwu HG and Henn F

    Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Kiel, Germany.

    The well-established role of genetic factors in the etiology of schizophrenia together with reports of allelic association with cPLA2, a phospholipase-A(2) gene, a reported increase of phospholipase-A(2) activity, and the phospholipase-A(2) hypothesis of Horrobin et al. [1995: Med Hypotheses 45:605-613] strongly support cPLA2 (PLA2G4A) and sPLA2 (PLA2G1B) as candidate genes for schizophrenia. In search for allelic association between these phospholipase-A(2) genes and schizophrenia, two samples of Chinese and European origins, in total 328 unrelated schizophrenic patients and their parents, were investigated using Falk and Rubinstein's haplotype relative risk method. Both genes showed marginally significant evidence for association in the total sample (P <or= 0.05), which, however, did not survive the Bonferroni correction for multiple testing. In conclusion, our results do not provide support for the phospholipase-A(2) hypothesis of schizophrenia. Additional studies will be necessary to rule out a possible confounding effect of niacin sensitivity as postulated by Hudson et al. [1999: Biol Psychiatr 46:401-405].

    American journal of medical genetics 2001;105;3;246-9

  • Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.

    Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K and Arinami T

    Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, 305-8575, Ibaraki, Japan.

    NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted.

    Molecular psychiatry 2001;6;2;211-6

  • An association study between polymorphism of L1CAM gene and schizophrenia in a Japanese sample.

    Kurumaji A, Nomoto H, Okano T and Toru M

    Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Japan. 0724.psyc@med.tmd.ac.jp

    L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

    American journal of medical genetics 2001;105;1;99-104

  • Polymorphism of the 5'-upstream region of the human SNAP-25 gene: an association analysis with schizophrenia.

    Tachikawa H, Harada S, Kawanishi Y, Okubo T and Suzuki T

    Department of Psychiatry, Kurita Hospital, Ibaraki, Japan. mg8@ea.mbn.or.jp

    Recent studies have suggested that synaptic abnormalities may be part of the pathophysiology of schizophrenia. SNAP-25 (synaptosomal-associated protein of 25 kD) is one of the synaptic proteins responsible for presynaptic neurotransmission, axonal elongation and synaptogenesis. Genetic variation in the 5'-upstream region of the SNAP-25 gene was analyzed in 87 unrelated schizophrenic patients and 100 healthy controls. A novel polymorphic (TAAA)(n) tandem repeat was identified in the 5'-upstream region. There were no significant differences between the patient and the control groups in the distribution of repeat numbers of alleles or genotypes. In addition, no associations were found between the polymorphism for subtypes, longitudinal courses or positive family history of the patients. Our results suggest that polymorphisms in the 5'-upstream region of the SNAP-25 gene have no association with schizophrenia.

    Neuropsychobiology 2001;43;3;131-3

  • Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia.

    Sakurai K, Toru M, Yamakawa-Kobayashi K and Arinami T

    Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, 305-8575, Ibaraki-ken, Japan.

    Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.

    Neuroscience letters 2000;296;2-3;168-70

  • Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia.

    Nishiguchi N, Shirakawa O, Ono H, Hashimoto T and Maeda K

    Department of Psychiatry and Neurology, Kobe University School of Medicine, Japan.

    Objective: N-methyl-D-aspartate (NMDA) receptor antagonists are known to produce a syndrome resembling schizophrenia, probably due to their blockade of NMDA receptors. The NMDA receptor 2B (NR2B) subunit has been identified as one of the major proteins in the postsynaptic density at glutamatergic synapses, suggesting that the carboxyl-terminal domain of the NR2B subunit may play a significant role in intracellular signal transduction.

    Method: The authors screened for genetic variations in the region of the NR2B subunit gene encoding the carboxyl-terminal intracellular domain in patients with schizophrenia and studied the association between schizophrenia and a novel polymorphism of the NR2B subunit gene.

    Results: One silent mutation (2664C/T) was identified. No significant differences in the frequencies of 2664C/T genotypes and alleles were found between patients with schizophrenia and healthy comparison subjects.

    Conclusions: The findings provided no evidence of an association between schizophrenia and the 2664C/T polymorphism of the NR2B subunit gene.

    The American journal of psychiatry 2000;157;8;1329-31

  • Association of the Ban I dimorphic site at the human cytosolic phospholipase A2 gene with schizophrenia.

    Peet M, Ramchand CN, Lee J, Telang SD, Vankar GK, Shah S and Wei J

    University Department of Psychiatry, Northern General Hospital, Sheffield, UK. m.peet@sheffield.ac.uk

    There is evidence of increased phospholipid breakdown in cell membranes of patients suffering from schizophrenia. This may be related to increased levels of the enzyme cytosolic phospholipase A2 (cPLA2) which have been reported in schizophrenic subjects. We have identified a Ban I dimorphic site on the first intron of the cPLA2 gene. Schizophrenic subjects were found to have a significant excess of the A2/A2 homozygote relative to healthy control subjects. Genetically determined alterations in phospholipase activity may thus underlie the reported abnormalities of phospholipid metabolism in schizophrenia.

    Psychiatric genetics 1998;8;3;191-2

  • Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia.

    Chen AC, Kalsi G, Brynjolfsson J, Sigmundsson T, Curtis D, Butler R, Read T, Murphy P, Petursson H, Barnard EA and Gurling HM

    Department of Psychiatry, University College London Medical School, U.K.

    Objective: Previous research has consistently implicated genetic factors in the pathogenesis of schizophrenia. It has been hypothesized that an abnormality in glutamatergic function is of etiologic importance in schizophrenia, and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis the authors sought to detect linkage between the GluR6 glutamate receptor gene and schizophrenia.

    Method: Twenty-three English and Icelandic families containing multiple cases of schizophrenia were genotyped with a microsatellite trinucleotide repeat polymorphism localized at the GluR6 glutamate receptor locus. Lod scores, model-free linkage analysis, and extended relative pair analysis were used to test for linkage.

    Results: No statistically significant evidence of linkage between GluR6 and schizophrenia was found.

    Conclusions: The results do not support the hypothesis that GluR6 allelic variants provide a major gene contribution to the etiology of schizophrenia in a large proportion of these pedigrees.

    Funded by: Wellcome Trust

    The American journal of psychiatry 1996;153;12;1634-6

Pubmed - other

  • N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.

    Martucci L, Wong AH, De Luca V, Likhodi O, Wong GW, King N and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, R-31, 250 College Street, Toronto (ON), Canada M5T 1R8.

    The NR2B protein is a critical structural and functional subunit of the NMDA glutamate receptor. The glutamate neurotransmitter system has been implicated in psychosis and schizophrenia, and so we looked for genetic association and measured gene expression in human DNA and brain samples, respectively, of the GRIN2B gene that codes for the NR2B protein. We tested three genetic polymorphisms: G-200T (5'UTR), A5806C and T5988C (both 3'UTR) in 180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms). We measured brain GRIN2B mRNA levels in schizophrenia, bipolar disorder and unaffected controls (n = 35 each). We detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.

    Schizophrenia research 2006;84;2-3;214-21

  • Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population.

    Washizuka S, Kametani M, Sasaki T, Tochigi M, Umekage T, Kohda K and Kato T

    Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama, Japan.

    Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11-13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, -3542G > A and -602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, -3542G > A and -602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter-individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;3;301-4

  • An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray.

    Qin S, Zhao X, Pan Y, Liu J, Feng G, Fu J, Bao J, Zhang Z and He L

    Bio-X Life Science Research Center, Shanghai Jiao Tong University, Shanghai 230030, PR China.

    Dysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005.

    European journal of human genetics : EJHG 2005;13;7;807-14

  • Extended analyses support the association of a functional (GT)n polymorphism in the GRIN2A promoter with Japanese schizophrenia.

    Iwayama-Shigeno Y, Yamada K, Itokawa M, Toyota T, Meerabux JM, Minabe Y, Mori N, Inada T and Yoshikawa T

    Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.

    Dysfunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. In this study, we extended our analyses, by increasing the number of case-control samples to a total of 672 schizophrenics and 686 controls, and excluded potential sample stratification effects. We confirmed the significant allelic association between the repeat polymorphism and disease (P = 0.011), and as in the previous study, we observed an over-representation of longer alleles in schizophrenia. These results suggest a probable genetic effect for the GRIN2A promoter (GT)n variation on the predisposition to schizophrenia in Japanese cohorts.

    Neuroscience letters 2005;378;2;102-5

  • No association of GSK3beta gene (GSK3B) with Japanese schizophrenia.

    Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y and Ozaki N

    Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. ikeda-ma@fujita-hu.ac.jp

    Several lines of evidence indicate that glycogen synthase kinase-3beta (GSK3beta) is one of the candidates for schizophrenia-susceptibility factor. However, it has not been reported the association analysis between GSK3beta gene (GSK3B) and Japanese schizophrenia based on linkage disequilibrium (LD). We provide an association analysis using relatively large samples (381 schizophrenia, and 352 controls) after determination of "tag single nucleotide polymorphisms (SNPs)." In this LD mapping, we selected and genotyped for eight polymorphisms (seven SNPs and one diallelic (CAA)(n) repeat), which covered the entire region of GSK3B, and determined two "tag SNPs." In the following association analysis using these two "tag SNPs," we could not find association with Japanese schizophrenia. Furthermore, we also include subgroup analysis considering age-at-onset and subtypes, neither could we find associations. Because our samples provided quite high power, these results indicate that GSK3B may not play a major role in Japanese schizophrenia.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005;134B;1;90-2

  • A family-based association study of PLP1 and schizophrenia.

    Qin W, Gao J, Xing Q, Yang J, Qian X, Li X, Guo Z, Chen H, Wang L, Huang X, Gu N, Feng G and He L

    Bio-X Life Science Research Center, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.

    Recently, proteolipid protein 1 (PLP1) has been identified as downregulated in schizophrenia by quantitative PCR and other technologies. In this work we attempted to investigate the role of PLP1 in the etiology of schizophrenia using a family based association study in 487 Chinese Han family trios. The TDT for allelic association demonstrated that, in male, a weak association was detected in SNP rs475827 with p=0.0294, suggesting that the genetic polymorphisms within PLP1 in male are likely to confer an increased susceptibility to schizophrenia in the Chinese population.

    Neuroscience letters 2005;375;3;207-10

  • Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia.

    Bah J, Quach H, Ebstein RP, Segman RH, Melke J, Jamain S, Rietschel M, Modai I, Kanas K, Karni O, Lerer B, Gourion D, Krebs MO, Etain B, Schürhoff F, Szöke A, Leboyer M and Bourgeron T

    Human Genetics and Cognitive Functions, Universite Paris 7, Institut Pasteur, 25, rue du docteur Roux, 75724 Paris Cedex 15, France.

    Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.

    Neuroreport 2004;15;12;1987-91

  • Association between schizophrenia and the syntaxin 1A gene.

    Wong AH, Trakalo J, Likhodi O, Yusuf M, Macedo A, Azevedo MH, Klempan T, Pato MT, Honer WG, Pato CN, Van Tol HH and Kennedy JL

    Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

    Background: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia.

    Methods: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families.

    Results: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2) = 5.898; df = 1; p =.015, family-based association test [FBAT] z = 2.280, p =.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z(c) = 2.859; p =.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP.

    Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.

    Biological psychiatry 2004;56;1;24-9

  • A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia.

    Verma R, Chauhan C, Saleem Q, Gandhi C, Jain S and Brahmachari SK

    Functional Genomics Unit, Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi University Campus, Delhi, India.

    Background: Chromosome 22q is one of the important regions repeatedly being implicated in schizophrenia. In this region, our group previously reported an association of a CAG repeat marker (22CH3) with schizophrenia in the Indian population. Because Synaptogyrin 1 (SYNGR1), associated with presynaptic vesicles in neuronal cells, lies within 1 million base pairs of this marker, it is a potential candidate gene for schizophrenia.

    Methods: We sequenced all six exons and flanking splice junctions of the SYNGR1 gene. We also carried out reverse transcriptase polymerase chain reaction and Northern blot analysis for exon 2 containing transcript of the SYNGR1 gene.

    Results: We found a novel nonsense mutation (Trp27Ter) in exon 2 of the SYNGR1 gene in a family multiply affected with schizophrenia. Reverse transcriptase polymerase chain reaction and Northern blot analyses revealed that exon 2 containing transcript of this gene is expressed in the brain.

    Conclusions: Because the SYNGR1 gene is involved in presynaptic pathways, reduced levels of this protein might play some role in the pathogenesis of schizophrenia.

    Biological psychiatry 2004;55;2;196-9

  • Association analysis for the CA repeat polymorphism of the neuronal nitric oxide synthase (NOS1) gene and schizophrenia.

    Liou YJ, Tsai SJ, Hong CJ and Liao DL

    Schizophrenia research 2003;65;1;57-9

  • Mutation and association analysis of the DAP-1 gene with schizophrenia.

    Aoyama S, Shirakawa O, Ono H, Hashimoto T, Kajimoto Y and Maeda K

    Department of Environmental Health and Safety, Kobe University Graduate School of Medicine, Kobe, Japan.

    Glutamate dysfunction has been hypothesized to be involved in the pathophysiology of schizophrenia. The human homolog of Drosophila discs large protein (hDLG) and post-synaptic density-95-associated protein-1 (DAP-1) is one of the major proteins that are involved in intracellular signal transduction via N-methyl-d-aspartate receptors. In the present study 33 Japanese patients with schizophrenia were screened for mutations in the DAP-1 gene. A single nucleotide polymorphism was identified in the DAP-1 gene (1618A/G). A case-control study using a larger sample of unrelated patients and controls did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the DAP-1 gene is involved in vulnerability to schizophrenia.

    Psychiatry and clinical neurosciences 2003;57;5;545-7

  • Mutation screening of the Homer gene family and association analysis in schizophrenia.

    Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.

    Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;120B;1;18-21

  • N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses.

    Martucci L, Wong AH, Trakalo J, Cate-Carter T, Wong GW, Macciardi FM and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, Toronto, Ontario, Canada.

    The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;119B;1;24-7

  • A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia.

    Itokawa M, Yamada K, Yoshitsugu K, Toyota T, Suga T, Ohba H, Watanabe A, Hattori E, Shimizu H, Kumakura T, Ebihara M, Meerabux JM, Toru M and Yoshikawa T

    Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.

    Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene. A case-control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P = 0.05, Mann-Whitney test), with longer alleles overly represented in patients. An in-vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)(n) repeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P = 0.01, Spearman's Rank test). These results illustrate a genotype-phenotype correlation in schizophrenia and suggest that the longer (GT)(n) stretch may act as a risk-conferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.

    Pharmacogenetics 2003;13;5;271-8

  • Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients.

    Hung CC, Chen HY and Chen CH

    Institute of Human Genetics, Tzu-Chi University, Hualien City, Taiwan. cchen@mail.tcu.edu.tw

    Schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population.

    Psychiatric genetics 2002;12;4;225-30

  • Alteration of branch site consensus sequence and enhanced pre-mRNA splicing of an NMDAR1 intron not associated with schizophrenia.

    Hammond L, Castanotto D, Rice SR, Nimgaonkar VL, Wirshing DA, Rossi JJ, Heston LL and Sobell JL

    Division of Molecular Medicine, City of Hope National Medical Center, Duarte, California 91010-0269, USA.

    Aberrant splicing of pre-mRNA is recognized to account for a significant minority of disease-causing mutations. The N-methyl-D-aspartate receptor (NMDA) subunit gene R1 (NMDAR1) is alternatively spliced to produce eight length variants. In an examination of the NMDAR1 as a candidate gene in schizophrenia, a presumed microdeletion/insertion (del/ins) was observed in intron 10 of an African-American male near a weak putative branch-site consensus sequence. Although exon 10 is not known to be alternatively spliced, the del/ins was posited to alter splicing efficiency. If splicing were abolished and intron retention occurred, an in-frame translation product of more than 250 amino acids was predicted. To explore splicing efficiency, mini genes were examined through primer-extension analyses in NIH293 embryonic kidney cell cultures. Rather than disruption of splicing, the del/ins allele exhibited a fivefold enhancement in splicing. In an association analysis with additional schizophrenic cases and unaffected controls, all of African-American descent, the mutant allele was observed at equivalent frequencies. A family study also did not support cosegregation of the variant allele with psychiatric disease.

    American journal of medical genetics 2002;114;6;631-6

  • Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia.

    Shinkai T, Ohmori O, Hori H and Nakamura J

    Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.

    Nitric oxide (NO) has been identified as a widespread and multifunctional biological messenger molecule in the central nervous system (CNS), with possible roles in neurotransmission, neurosecretion, synaptic plasticity, and tissue injury in many neurological disorders, including schizophrenia. Neuronal NO is widely produced in the brain from L-arginine catalyzed by neuronal NO synthase (NOS1). We therefore hypothesized that the NOS1 gene may play a role in the pathophysiology of schizophrenia. In the present study, we examined the genetic association between a novel single nucleotide polymorphism (SNP: a C-->T transition located 276 base pairs downstream from the translation termination site) of the human NOS1 gene, which is located in chromosome 12q24, and schizophrenia (215 Japanese patients with schizophrenia and 182 healthy controls). The allele frequencies of the polymorphism in exon 29 of the NOS1 gene differed significantly between patients with schizophrenia and controls (chi(2) = 20.10, df = 1, P = 0.000007; relative risk = 1.92; 95% confidence interval = 1.44-2.55). Our results suggest that the NOS1 gene polymorphism may confer increased susceptibility to schizophrenia.

    Molecular psychiatry 2002;7;6;560-3

© 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).

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