Lack of replication in SAGE does not exclude the possibility that some previously proposed candidate genes and specific loci are biologically important. Several of the most well studied candidate loci for alcoholism were not available in SAGE, including rs671 in ALDH2, rs1229984 in ADH1B, rs4795541 in SLC6A4 and rs3813867 in CYP2E1. A recent study that specifically genotyped rs1229984 in SAGE reported that the minor allele has a significant protective effect on alcohol dependence (p=6.6× 10−10) (Bierut et al., 2011). Because rs1229984 is common in Asians but rare in European Americans, this variant in ADH1B was not genotyped in the original GWA study. This highlights that GWA studies may miss important variants because of lack of coverage of SNPs that are uncommon in European American populations. Additionally, GWA studies cannot assess all forms of inheritance that can be associated with candidate genes such as insertion/deletion mutations, copy number repeats and epigenetic changes. Although SAGE is a valuable tool, it cannot exclude the possibility that aspects of genes contribute to genetic risk of alcohol dependence.
