G2Cdb::Human Disease report

Disease id
D00000177
Name
Autism
Nervous system disease
yes

Genes (5)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001796 MAP2
microtubule-associated protein 2
Y (14986829) Deletion (D) ?
G00001434 RAF1
v-raf-1 murine leukemia viral oncogene homolog 1
Y (16648338) Single nucleotide polymorphism (SNP) N
G00001434 RAF1
v-raf-1 murine leukemia viral oncogene homolog 1
Y (16263864) Single nucleotide polymorphism (SNP) Y
G00001434 RAF1
v-raf-1 murine leukemia viral oncogene homolog 1
Y (16205742) Single nucleotide polymorphism (SNP) N
G00001434 RAF1
v-raf-1 murine leukemia viral oncogene homolog 1
Y (15056512) Single nucleotide polymorphism (SNP) Y
G00000031 HRAS
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
Y (8832771) Repeat polymorphism (RP) Y
G00001468 RAB3A
RAB3A, member RAS oncogene family
Y (15005721) Unknown (?) N
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (11920157) Single nucleotide polymorphism (SNP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (15389769) Single nucleotide polymorphism (SNP) Y

References

  • Lack of association between autism and SLC25A12.

    Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR and Pericak-Vance MA

    Center for Human Genetics, Department of Medicine, Duke University Medical Center, 595 LaSalle St., Durham, NC 27710, USA.

    Objective: Autism has a strong, complex genetic component, most likely involving several genes. Multiple genomic screens have shown evidence suggesting linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Recently, an association between autism risk and two single nucleotide polymorphisms (SNPs) in SLC25A12 was reported. This study aimed to test for association in SLC25A12 in an independent data set of 327 families with autistic offspring.

    Method: The authors analyzed two SNPs that were significant in the previous study group, as well as seven additional SNPs within the gene. Association analyses for individual SNPs as well as haplotypes were performed.

    Results: There was no evidence of an association between SLC25A12 and autism.

    Conclusions: These results suggest that SLC25A12 is not a major contributor to autism risk in these families.

    Funded by: NCRR NIH HHS: RR-00095; NINDS NIH HHS: NS-26630, NS-36768

    The American journal of psychiatry 2006;163;5;929-31

  • SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample.

    Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E and International Molecular Genetic Study of Autism Consortium (IMGSAC)

    Department of Biology, University of Bologna, Bologna, Italy.

    Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus of candidate gene and association studies. Recently, significant association with autism has been reported for single-nucleotide polymorphisms (SNPs) in the SLC25A12 and CMYA3 genes on chromosome 2q. We attempted to replicate these findings in the collection of families from the International Molecular Genetic Study of Autism Consortium (IMGSAC), using the transmission disequilibrium test and case-control comparison. Our study failed to reveal any significant association for the SNPs tested at either locus, suggesting that these variants are unlikely to play a major role in genetic susceptibility to autism in our sample.

    Funded by: Telethon: GGP030227; Wellcome Trust

    European journal of human genetics : EJHG 2006;14;1;123-6

  • Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31.

    Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M and Gallagher L

    Department of Genetics, Trinity College, Dublin 2, Ireland. rsegurdo@tcd.ie

    Objective: Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings.

    Method: Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism.

    Results: In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype.

    Conclusions: These findings provide replication of the association between autism and SLC25A12.

    The American journal of psychiatry 2005;162;11;2182-4

  • Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

    Shuang M, Liu J, Jia MX, Yang JZ, Wu SP, Gong XH, Ling YS, Ruan Y, Yang XL and Zhang D

    Institute of Mental Health, Peking University, Beijing, China.

    The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;131B;1;48-50

  • DNA variants in the human RAB3A gene are not associated with autism.

    D'Adamo P, Bacchelli E, Blasi F, Lipp HP, Toniolo D and Maestrini E

    Institute of Anatomy, University of Zurich, Switzerland. p.dadamo@anatom.unizh.ch.

    Mutation screening of the RAB3A gene in 47 individuals with autism provided no evidence that DNA variants in this gene are associated with autism. Since Rab3a constitutive knockout mice react to novel stimuli with hyperactivity, a further search for association of RAB3A DNA variants with other neurobehavioral disorders such as attention deficit/hyperactivity disorder appears justified.

    Funded by: Telethon: E.1007, GGP030192

    Genes, brain, and behavior 2004;3;2;123-4

  • Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

    Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL and Buxbaum JD

    Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

    Objective: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region.

    Method: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families.

    Results: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci.

    Conclusions: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

    Funded by: NIMH NIH HHS: U54 MH066673; OMHHE CDC HHS: MN-066673

    The American journal of psychiatry 2004;161;4;662-9

  • Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.

    Pescucci C, Meloni I, Bruttini M, Ariani F, Longo I, Mari F, Canitano R, Hayek G, Zappella M and Renieri A

    Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.

    We present here a unique case of a 14-year-old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand-washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down-slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case.

    Funded by: Telethon: GGP02372, GTF02006

    Clinical genetics 2003;64;6;497-501

  • Linkage and association of the glutamate receptor 6 gene with autism.

    Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T and Paris Autism Research International Sibpair (PARIS) Study

    Laboratoire d'Immunogénétique Humaine, INSERM E021, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris cedex 15, France.

    A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

    Molecular psychiatry 2002;7;3;302-10

  • Studies of the c-Harvey-Ras gene in psychiatric disorders.

    Comings DE, Wu S, Chiu C, Muhleman D and Sverd J

    Department of Medical Genetics, City of Hope National Medical Center, Duarte, CA 91010-0269, USA.

    Hérault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive-compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Hérault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders.

    Psychiatry research 1996;63;1;25-32

Literature (9)

Pubmed - human_disease

  • SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample.

    Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E and International Molecular Genetic Study of Autism Consortium (IMGSAC)

    Department of Biology, University of Bologna, Bologna, Italy.

    Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus of candidate gene and association studies. Recently, significant association with autism has been reported for single-nucleotide polymorphisms (SNPs) in the SLC25A12 and CMYA3 genes on chromosome 2q. We attempted to replicate these findings in the collection of families from the International Molecular Genetic Study of Autism Consortium (IMGSAC), using the transmission disequilibrium test and case-control comparison. Our study failed to reveal any significant association for the SNPs tested at either locus, suggesting that these variants are unlikely to play a major role in genetic susceptibility to autism in our sample.

    Funded by: Telethon: GGP030227; Wellcome Trust

    European journal of human genetics : EJHG 2006;14;1;123-6

  • Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31.

    Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M and Gallagher L

    Department of Genetics, Trinity College, Dublin 2, Ireland. rsegurdo@tcd.ie

    Objective: Autism is a neurodevelopmental disorder with childhood onset and a known major genetic component. A recent study identified a highly significant association between autism and a two-single-nucleotide-polymorphism haplotype in the SLC25A12 gene, with a homozygote genotype relative risk between 2.4 and 4.8. The authors' goal was to investigate this association with autism in Irish affected child-parent trios because replication in an independent sample is essential in the validation of such potentially important findings.

    Method: Markers rs2056202 and rs2292813 were genotyped in a total of 158 trios (442 individuals). The Transmission Disequilibrium Test was used to examine these markers for association with autism.

    Results: In agreement with the recent study, the authors found significant association between autism and the C alleles of both rs2056202 and rs2292813 as well as the two-marker haplotype.

    Conclusions: These findings provide replication of the association between autism and SLC25A12.

    The American journal of psychiatry 2005;162;11;2182-4

  • Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

    Shuang M, Liu J, Jia MX, Yang JZ, Wu SP, Gong XH, Ling YS, Ruan Y, Yang XL and Zhang D

    Institute of Mental Health, Peking University, Beijing, China.

    The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;131B;1;48-50

  • Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.

    Pescucci C, Meloni I, Bruttini M, Ariani F, Longo I, Mari F, Canitano R, Hayek G, Zappella M and Renieri A

    Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.

    We present here a unique case of a 14-year-old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand-washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down-slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case.

    Funded by: Telethon: GGP02372, GTF02006

    Clinical genetics 2003;64;6;497-501

  • Studies of the c-Harvey-Ras gene in psychiatric disorders.

    Comings DE, Wu S, Chiu C, Muhleman D and Sverd J

    Department of Medical Genetics, City of Hope National Medical Center, Duarte, CA 91010-0269, USA.

    Hérault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive-compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Hérault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders.

    Psychiatry research 1996;63;1;25-32

Pubmed - other

  • Lack of association between autism and SLC25A12.

    Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR and Pericak-Vance MA

    Center for Human Genetics, Department of Medicine, Duke University Medical Center, 595 LaSalle St., Durham, NC 27710, USA.

    Objective: Autism has a strong, complex genetic component, most likely involving several genes. Multiple genomic screens have shown evidence suggesting linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Recently, an association between autism risk and two single nucleotide polymorphisms (SNPs) in SLC25A12 was reported. This study aimed to test for association in SLC25A12 in an independent data set of 327 families with autistic offspring.

    Method: The authors analyzed two SNPs that were significant in the previous study group, as well as seven additional SNPs within the gene. Association analyses for individual SNPs as well as haplotypes were performed.

    Results: There was no evidence of an association between SLC25A12 and autism.

    Conclusions: These results suggest that SLC25A12 is not a major contributor to autism risk in these families.

    Funded by: NCRR NIH HHS: RR-00095; NINDS NIH HHS: NS-26630, NS-36768

    The American journal of psychiatry 2006;163;5;929-31

  • DNA variants in the human RAB3A gene are not associated with autism.

    D'Adamo P, Bacchelli E, Blasi F, Lipp HP, Toniolo D and Maestrini E

    Institute of Anatomy, University of Zurich, Switzerland. p.dadamo@anatom.unizh.ch.

    Mutation screening of the RAB3A gene in 47 individuals with autism provided no evidence that DNA variants in this gene are associated with autism. Since Rab3a constitutive knockout mice react to novel stimuli with hyperactivity, a further search for association of RAB3A DNA variants with other neurobehavioral disorders such as attention deficit/hyperactivity disorder appears justified.

    Funded by: Telethon: E.1007, GGP030192

    Genes, brain, and behavior 2004;3;2;123-4

  • Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

    Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL and Buxbaum JD

    Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.

    Objective: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region.

    Method: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families.

    Results: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci.

    Conclusions: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

    Funded by: NIMH NIH HHS: U54 MH066673; OMHHE CDC HHS: MN-066673

    The American journal of psychiatry 2004;161;4;662-9

  • Linkage and association of the glutamate receptor 6 gene with autism.

    Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T and Paris Autism Research International Sibpair (PARIS) Study

    Laboratoire d'Immunogénétique Humaine, INSERM E021, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris cedex 15, France.

    A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

    Molecular psychiatry 2002;7;3;302-10

© 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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