Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism

Abstract

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.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…No association for SNPs in the GABA receptor genes on chromosome 15 were found. 220 Similar inconclusive results have been obtained for variants in or close to the AT Pase, class V, type 10C (ATP10C) and the ubiquitin-protein ligase E3A (UBE3A) genes located in the maternal expression domain of chromosome 15q11-13. 212,221,222 Only one study 223 reported an association of D15S122/ hCV2558436 located in the intron at the 5 0 end of UBE3A, which remained significant after correction for multiple testing.…”

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

“…Furthermore, genetic and environmental interactions may also contribute to the autism phenotype. 20,21 In addition, the inclusion of heterogeneous phenotypes may explain the lack of consistency of results in the study of autism. Genomewide linkage scans that stratify subjects into more homogeneous phenotypes have shown striking differences in linkage results, including differences by the strictness of the definition of autism, 16,22 sex, 16,23 developmental regression, 16,24 language delay 25,26 and repetitive behaviors.…”

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

“…Significant findings have been observed for autism and bipolar disorder in candidate gene association studies for GABA A receptor subunit genes on 4p12 and 15q12, 11,12 and for GABRB1, GABRA4, GABRB3, GABRA5 and GABRR3 in the Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder. Mutations in several GABA A genes are known to cause various epilepsies, including GABRG2 in childhood absence epilepsy or generalized epilepsy (with or without febrile seizures) 13,14 and GABRA1 causing juvenile myoclonic epilepsy.…”