Other early genetic studies of alcohol dependence relied on candidate gene association studies and genome-wide linkage studies. Candidate gene studies leveraged the earliest identified genetic variations in specific genes by examining one gene, and often one variant, at a time to determine whether the variant was associated with alcoholism. These experiments identified hundreds of genes as potentially contributing to alcoholism. For example, in addition to the genes encoding alcohol-metabolizing enzymes, genes involved in brain signaling (i.e., neurotransmitter) systems, such as the dopaminergic, cholinergic, and serotonergic systems, have been nominated for their association with alcohol dependence. In contrast to the alcohol-metabolizing genes, however, these other candidate gene associations have not yet been validated in the modern large-scale genetic studies. This lack of convergence of candidate gene studies and GWASs potentially reflects a large number of false-positive findings from the previous candidate gene findings. Another potential explanation is that extensive genetic heterogeneity exists, meaning that multiple genes each modestly contribute to the development of alcohol dependence and that the samples collected to date, although they were obtained from thousands of subjects, are not yet sufficient in size to detect variation in these regions.
