Gamma-Aminobutyric Acid System Genes-No Evidence for a Role in Alcohol Use and Abuse in a Community-Based Sample

Background: While twin and adoption studies point to substantial genetic influence upon alcohol use, dependence, and other alcohol-related phenotypes, few of the genes underlying variation in these phenotypes have been identified. Markers in genes related to GABAergic activity-a system integral to many of alcohol's biological effects-have been implicated in alcohol use and alcohol-related psychopathology in linkage and association studies. Methods: Using multiple methods, we conducted a comprehensive examination of the effects of markers in γ-aminobutyric acid (GABA) system genes in a community-based sample of 7,224 individuals assessed in early and middle adulthood. In addition to testing the effect of individual single nucleotide polymorphism (SNP) markers on alcohol-related phenotypes, we computed a polygenic score reflecting the aggregated effects of multiple GABA system SNPs. We also estimated the variance in alcohol-related phenotypes attributable to all GABA system markers considered simultaneously and conducted gene-based association tests. Results: No method produced results indicative of an effect of GABA system variants on measures of alcohol use or misuse. Conclusions: These results reflect alcohol-related behaviors in a population-representative sample, many of whom are still in adolescence, and in which the incidence of heavy drinking and alcohol-related symptomatology are relatively low. Contrasted with existing studies of the association between alcohol use and GABA system genes, our results suggest that the relationship may be limited to particular contexts, such as when accompanied by polysubstance abuse or a familial history of alcoholism.