Analysis of GABA(A) receptor subunit genes in alcohol dependence and anxiety disorders.

摘要

The major objective of this study was to evaluate, using polymorphism detection and linkage strategies, the role of genetic variation of γ-aminobutyric acid type A (GABAA) receptor genes in the genetic susceptibility to alcohol dependence (AD). In addition, the role of GABRG2 in the genetic susceptibility to obsessive-compulsive disorder (OCD), a severe anxiety disorder, was analyzed.; Sequence variants of the GABRA1, GABRA6, GABRB2 and GABRG2 genes, on chromosome 5q, and of GABRB1 on 4p, were detected by pDHPLC. The sensitivity and specificity of this novel method was first tested in double-blind fashion across 9 known single nucleotide polymorphisms (SNPs). A total of 12,412,896 by from genomic DNA (that is, 8,342 by x 1,488 chromosomes) was scanned for variation. Putative variants were confirmed and characterized by automated sequencing. A panel of six SNPs at the 5q cluster was selected for linkage and association studies and genotyped blind to diagnosis by PCR-RFLP.; For AD, two large psychiatrically interviewed samples from population isolates were used: A Southwestern American-Indian (SWAI) tribe (N = 418) and a Finnish sample (N = 473). No deviation of genotypic distributions from Hardy-Weinberg equilibrium was detected. Association of GABRB2 and GABRA6 with AD was detected in both samples. Sib-pair linkage of GABRG2 to AD was detected in the Finnish sample only. Linkage disequilibrium (LD) between alleles at the six loci did not vary as a simple function of loci distance, and normalized LD coefficients varied between them. The trimmed haplotype analysis showed evidence of linkage of 5q GABAA haplotypes to AD. These results are consistent with genetic variation at or near the 5q GABAA cluster conferring differential susceptibility to alcohol dependence.; To investigate the role of the GABRG2 gene in OCD, subjects and controls from the US (N = 96) and Italy (N = 92) were genotyped blind to diagnoses for two GABRG2 SNPs. No significant deviation from Hardy-Weinberg equilibrium was found in either sample. Population association was detected between both SNPs and OCD in both samples. These results suggest that either these polymorphisms alter function, or that they are in linkage disequilibrium with a functional variant that confers increased genetic vulnerability to OCD.