The strong effect of ADH1B and ADH1C coding variants may obscure more modest effects of regulatory variants. Coding SNPs that lead to more active ADH enzymes are protective, so it is logical to anticipate that regulatory variants that increase expression of those enzymes have a similar, if more modest, effect. Individual SNPs and haplotypes have been shown to affect expression of ADH genes, including ADH1B (Pochareddy and Edenberg, 2011), ADH1C (Chen et al., 2005), ADH4 (Edenberg et al., 1999, Pochareddy and Edenberg, 2010), and ADH7 (Jairam and Edenberg, 2014a, Jairam and Edenberg, 2014b). Some mapped regulatory elements that affect ADH1B expression in liver-derived cells lie in the region between ADH1B and ADH7 (Chen et al., 2005, Jairam and Edenberg, 2014a, Jairam and Edenberg, 2014b). There are many eQTLs, extending broadly across the region, that affect expression of one or more ADH genes. These differ in different tissues; for example, in subcutaneous adipose there is a dense cluster between ADH7 and ADH1C and a small cluster over 700 kb away, whereas in visceral adipose there is a cluster between ADH4 and ADH6, extending beyond ADH5 (Supplementary Figure 1).
