Despite these caveats, the GWAS described in Table 1 have already vastly expanded our understanding of the genetic architecture of alcohol use behaviors. It is evident that alcohol use behaviors, like all complex traits, are highly polygenic (11). The proportion of variance explained by genetic variants on GWAS chips (SNP-heritability) ranges from 4 to 13% (Figure 4). It is possible that a significant portion of the heritability can be explained by SNPs not tagged by GWAS chips, including rare variants (46). For instance, a recent study showed that rare variants explained 1–2% of phenotypic variance and 11–18% of total SNP heritability of substance use phenotypes (72). Nonetheless, rare variants are often not analyzed when calculating SNP heritability, which can lead to an underestimate of polygenic effects, as well as missing biologically relevant contributions for post-GWAS analyses (73). Equally important is the need to include other sources of -omics data when interpreting genetic findings, and the need to increase population diversity (see Supplemental 2). Therefore, a multifaceted approach targeting both rare and common variation, including functional data, and assembling much larger
