We explore one gene that illustrates the complexities and the progress being made in understanding sources of risk for alcohol dependence. GABAA subtype receptors are sensitive to ethanol and mediate several of its behavioral effects (including anxiolysis)71. The region around a cluster of GABAA receptor subunit genes on chromosome 4 was implicated originally by linkage studies in Native American72 and the Collaborative Study on the Genetics of Alcoholism (COGA) family samples73. The GABAA receptor α2 subunit (GABRA2) gene in this cluster became the focus of substantial attention when a three-SNP haplotype was strongly associated with adult alcohol dependence (P = 2.2 × 10−8) and with an electrophysiological endophenotype in family based association in the same sample74. The risk haplotype confers ~1.2 times the risk of developing alcohol dependence, but no high-risk haplotype coding sequence variation was detected. The association with alcohol dependence risk was replicated in United States75 and Russian76 samples, and this risk due to GABRA2 variants is moderated by variables including marital status and anxiety77,78.
