Background: Evidence from human, animal, and in vitro cell models suggests that �-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABA A receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive. Methods: We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABA A receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABA A receptor genes: GABRA5, GABRB3, and GABRG3. Results: Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes. Conclusions: These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA
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