GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA-A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90kb distant in the 3′ direction. Due to strong linkage disequilibrium in European-Americans, the origin, or origins, of the association signal are very difficult to discern, but our previous population-based study suggested that decreased LD across the GABRG1- GABRA2 region in African-Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population.
Methods & Results
To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls. Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3-SNP GABRA2 haplotype (global p=0.00029). A similar level of significance was obtained in 6-SNP haplotypes that combined tagging SNPs from both genes (global p=0.00994). High statistical significance was also shown with a 6-SNP haplotype (T-G-C-G-T-A), p=0.0033. The T-G-C-G-T-A haplotype contains the most significant GABRA2 3-SNP haplotype (p= 0.00019), G-T-A.
These findings reflect the interrelationship of these two genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a European-American population, owing to the much lower linkage disequilibrium across these loci in AAs.