Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis

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Abstract
Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the α2 subunit of the γ-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3′ end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. The overall alcohol-dependent patients vs. control group comparison confirmed positive allelic association for five of six single-nucleotide polymorphisms mapping from intron 3 to the 3′ end of GABRA2 (P=0.01–0.02). Haplotype analysis revealed two common haplotypes accounting for approximately 90% of the chromosomes within the patients and controls. The less frequent haplotype was significantly more prevalent among the alcohol-dependent patients (45%) than among the controls [29%; odds ratio (OR)=1.97, 95% confidence interval (CI): 1.30–2.96]. The strength of association increased, if the subsets of alcohol-dependent patients with a positive family history (OR=2.60, 95% CI: 1.63–4.13), withdrawal seizures (OR=2.22, 95% CI: 1.30–3.79) or an early onset (OR=2.19, 95% CI: 1.24–3.88) were analyzed. Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population. We found a consistent increase of the susceptibility effect in alcohol-dependent patients with a presumed strong genetic predisposition.