Many other variations in and around the seven ADH genes have been associated with risk for alcohol dependence or alcohol-related traits. Among these, variations in and near ADH4 are among the most widely replicated associations with alcohol dependence, in several populations. Moreover, noncoding SNPs in the region of ADH1A, ADH1B, and ADH1C have been associated with alcoholism and drinking phenotypes, as have SNPs in ADH7 and ADH5. Some non-coding SNPs have been shown to affect gene expression in cultured cells and tissues (i.e., in vitro) (Chen et al 2005; Pochareddy and Edenberg 2010, 2011), and it is likely that many different variations in this region also affect the level of expression of the different ADH enzymes in the intact organism (i.e., in vivo), thereby influencing ethanol metabolism (in some cases possibly only in specific tissues), its physiological effects, and, ultimately, drinking behavior and risk for alcoholism. Without molecular studies, however, detailed analyses of which SNPs might be functional are difficult because many of the ADH variations are inherited together with nearby SNPs as haplotypes.
