The Role of GABRA2 in Alcohol Dependence, Smoking, and Illicit Drug Use in an Australian Population Sample

Abstract

Multiple studies have shown that genetic variation in the alpha-2 subunit of the gamma-aminobutyric acid type A (GABA(A)) receptor (GABRA2) is associated with risk for alcohol dependence. Recent reports have suggested that GABRA2 may exert its influence on dependence through factors such as sensitivity to alcohol's intoxicating effects and that GABRA2 may also contribute to a common underlying genetic vulnerability to both alcohol and drug dependence. The present study tested for association between GABRA2 and alcohol dependence, smoking, and illicit drug use within the Australian population. We genotyped 11 single nucleotide polymorphisms (SNPs) within or flanking GABRA2 in 4597 subjects (34.6% males) from 2618 families comprising 814 monozygotic pairs, 1177 dizygotic pairs, and 627 twins whose co-twin did not participate. Family-based association tests were conducted for binary and quantitative measures of alcohol dependence, smoking, and cannabis and other illicit drug use. We observed evidence of association (p < 0.05) between multiple GABRA2 SNPs and quantitative measures of alcohol dependence, including symptom scores and principal component factor scores from the 9 criteria for DSM-IV alcohol dependence, in the opposite direction to that previously reported. In contrast, GABRA2 was not associated overall with dichotomous measure of alcohol dependence nor with smoking, cannabis, or illicit drug use. The GABRA2 allelic associations found in clinical case-control studies have detectable but minor effects on DSM-defined alcohol dependence in the general community. Systematic comparisons of allelic effects on alcohol dependence in clinical cases and in the general community are required.