With the advent of microarrays that can measure hundreds of thousands to millions of single nucleotide polymorphisms (SNPs) across the genome, genome-wide association studies (GWAS) have provided a relatively unbiased way to identify specific genes that contribute to a phenotype. To date, GWAS have focused on common variants, with allele frequencies of 5% or higher. Most GWAS are case-control studies or studies of quantitative traits in unrelated subjects, but family-based GWAS provide another approach. GWAS are beginning to yield robust findings, although the experience in many diseases is that very large numbers of subjects will be needed. To date, individual GWAS studies on alcohol dependence and related phenotypes have been relatively modest in size, and most do not reach genome-wide significance. This may reflect both the limited sample sizes and the clinical and genetic heterogeneity of the disease. As noted above, the functional ADH1B polymorphism is not represented on GWAS platforms; GABA-receptor genes are often nominally significant but well below genome-wide significance in these studies. Thus, the genes and SNPs found through GWAS have had little overlap with previous findings based on candidate genes/pathways and linkage analyses.
