GWASs of AD and related phenotypes have identified numerous loci, however, these loci alone have limited utility (i.e., they each account for less than 1% of the variance in liability of the disease/trait). Despite this limitation, alcohol GWAS continue to be studied because they (1) support pathways that were previously hypothesized from linkage study findings, and (2) highlight pathways that were not initially considered (Heath et al., 2011); for example, genes involved in the specification and maintenance of neuronal connections. The major success and challenge of alcohol GWAS is that hundreds of genetic variants, each with a modest effect size, contribute to its liability. This observation presents several new challenges to modeling the relationships between different genes and alcohol phenotypes, such as (1) the identification and selection of polymorphisms, (2) reducing the heterogeneity of alcohol phenotypes, (3) the design and implementation of mathematical approaches that provide the necessary power, and (4) the development of a conceptual framework that will provide a meaningful interpretation of the findings. For the remainder of the paper we discuss factors as they relate to the missing heritability in alcohol GWAS.
