We used multiple methods to examine the influence of markers in GABA system genes on measures of alcohol use and alcohol abuse and dependence symptomatology. In addition to GABAA receptor subunit genes, markers in a number of which have been previously associated with alcohol-related phenotypes, we also considered markers in and near genes involved in the synthesis, release, transport, and metabolism of GABA, as well as other activity related to GABA or GABA receptors. First, because individual variants conveying risk for elevated alcohol use may be of such minute effect that markers in linkage with risk alleles may fail to exceed thresholds for significance in single-SNP analyses, we calculated a polygenic score reflecting variation in alcohol use phenotypes attributable to the combined set of linkage disequilibrium (LD) pruned GABA system SNPs, at several significance thresholds. Next, we derived an estimate of the phenotypic variance explained by the GABA SNPs in this set, from a SNP-based estimate of genetic similarity between pairs of participants who are not close genetic relatives. Finally, we examined the effect of individual GABA system genes using a gene-based test.
