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تاريخ التسجيل: Dec 2011
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Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism

D.Q. Ma1, P.L. Whitehead1, M.M. Menold1, E.R. Martin1, A.E. Ashley-Koch1, H. Mei3, M.D. Ritchie4, G.R. DeLong2, R.K. Abramson5, H.H. Wright5, M.L. Cuccaro1, J.P. Hussman6, J.R. Gilbert1, M.A. Pericak-Vance1, ,
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doi:10.1086/433195
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Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2,GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis—with the pedigree disequilibrium test and the family-based association test—and for genotypic and haplotypic association analysis—with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.

Introduction
Autistic disorder (MIM 209850) is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication and the presence of restricted and repetitive patterns of interest or behavior. These impairments are apparent in the first 3 years of life and persist into adulthood. With the improved detection and recognition of autism that has resulted from a broadening of the diagnostic concept and systematic population approaches, a recent prevalence study reported that autistic disorder affects as many as 1 in 300 children in a U.S. metropolitan area (Yeargin-Allsopp et al. 2003). The increase in prevalence has drawn significant attention from scientists, and a rapid increase in the level of interest in the etiology of autism has been seen in the past decade (Fombonne 1999, 2003).

Autism has turned out to be one of the most heritable complex genetic disorders in psychiatry. A strong genetic component in autism is indicated by an increased concordance rate in MZ twins (60% and 91% for the narrow and broad phenotypes, respectively), compared with that in DZ twins (0% and 10% for the narrow and broad phenotypes, respectively) (Steffenburg et al. 1989; Bailey et al. 1995), and by a 75-fold greater risk to siblings of idiopathic cases, in comparison with the risk to the general population (Bolton et al. 1994). Collectively, these studies suggest that autistic disorder involves multiple variants in multiple unlinked loci that interact to cause the autism phenotype. In addition to genetic risk-assessment studies, both direct mapping approaches (chromosomal methods and linkage and association studies) and indirect mapping approaches (the characterization of disorders that share some of the symptoms of autism, such as Rett or fragile X syndrome) have been applied to identify autism-susceptibility genes. These studies have also yielded convincing evidence for the multigenic inheritance and the locus or allelic heterogeneity in autism.

Over 10 genomewide autism screens have been performed (International Molecular Genetic Study of Autism Consortium 1998, 2001; Meyers et al. 1998; Philippe et al. 1999; Risch et al. 1999; Collaborative Linkage Study of Autism 2001; Liu et al. 2001; Auranen et al. 2002; Shao et al. 2002; Yonan et al. 2003). Results from these various screens indicate potential susceptibility genes spread across the entire genome. Estimates of the number of genes involved in autism range from 3–10 (Pickles et al. 1995; Folstein and Rosen-Sheidley 2001) to ⩾15 (Risch et al. 1999) to 100 (Pritchard 2001). Numerous association studies of the candidate genes have been conducted on the basis of location in a linkage peak or potential function, but no single gene has been consistently replicated across studies. One explanation for the lack of consistency in association studies is that there are many contributing genetic and environmental factors in autism. Moreover, multiple interacting genes may be the main causative determinants of autism (Muhle et al. 2004; Veenstra-VanderWeele et al. 2004). With only a modest sample size, a small-to-moderate locus effect is not easily detected. Therefore, tests for joint effects may be more successful in the search for autism-susceptibility genes.

 

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