Establishing robust statistical evidence for a GWAS-identified variant marks the starting point in the path to elucidating its biological consequences as related to disease outcomes. Its annotation in the context of DNA, RNA, and protein sequences often provides the first clue. Coding SNPs that alter the protein’s amino acid sequence can be undoubtedly important for risk of developing complex human diseases, including addiction (e.g., CHRNA5 SNP rs16969968 for smoking [Table 1] and ADH1B SNP rs1229984 and ALDH2 SNP rs671 for alcohol [Table 2]). However, >95% of GWAS discoveries come from noncoding SNPs [131]. Noncoding SNPs can alter gene activity by influencing DNA methylation, RNA expression, protein expression, or metabolite levels and are thus well-recognized for their disease risk potential. Indeed, the GWAS catalog is heavily enriched for regulatory variants, such as eQTLs [131–133], and variants residing in sequences that are highly conserved, sensitive to cleavage by DNase I, or mark enhancer, promoter, or protein binding sites [133].
