A role for the GABA/benzodiazepine receptor complex in alcohol dependence syndrome has been suggested by several lines of evidence. To elucidate the role of GABA(A) subunits in human alcohol dependence syndrome, we identified polymorphisms in the GABA(A)β2 and GABA(A)α6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a Ncλ RFLP at the GABA(A)γ2 receptor subunit gene. One hundred and eight alcohol-dependent subjects and 54 unrelated controls were recruited from Scotland. Two novel genetic markers were identified at the GABA(A)β2 and GABA(A)α6 receptor subunit genes and examined for association with the alcohol dependence syndrome and subgroups of subjects with Korsakoff's psychosis and without Korsakoff's psychosis, together with a Ncλ RFLP at the GABA(A)γ2 receptor subunit gene. The χ2 tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the Banl RFLP at the GABA(A)β2 receptor subunit gene (P = 0.015), and the AlwNI RFLP at the GABA(A)α6 receptor gene (P = 0.013). Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the Banl RFLP (P = 0.039) and the AlwNI RFLP (P = 0.003). Haplotype analysis also provided evidence of association when all alcohol-dependent subjects (P = 0.013) and the subjects with Korsakoff's psychosis (P = 0.007) were compared with controls. Our findings provide evidence for a role for the GABA(A) receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis.
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