Association between variants at the GABA_Aβ2, GABA_Aα6 and GABA_Aγ2 gene cluster and alcohol dependence in a Scottish population

Abstract

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_Aβ2 and GABA_Aα6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a NciI RFLP at the GABA_Aγ2 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_Aβ2 and GABA_Aα6 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 NciI RFLP at the GABA_Aγ2 receptor subunit gene. The χ² tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABA_Aβ2 receptor subunit gene (P = 0.015), and the AlwNI RFLP at the GABA_Aα6 receptor gene (P = 0.013). Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the BanI 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.