We identified an unusual instance of Hardy-Weinberg disequilibrium (HWD). ADH1B rs1229984, the most consistently associated alcohol risk variant in European populations (16), was initially excluded from analysis because it deviated from Hardy-Weinberg equilibrium expectations (HWEE) (p=1.46e-43). This variant is functional (32), presents very strong allele frequency differences among human populations (33), and has undergone selection in Asian and European populations (17, 34), although there is an open debate about the presence of convergent evolution in Europeans (35). Since ADH1B rs1229984 is the most relevant locus associated with alcohol drinking behaviors that has a very well established causative mechanism (17), we investigated the cause for HWD further to avoid unnecessary exclusion of this variant, which would have highlighted the association of other variants in the same region due to the LD without reflecting the real causal mechanism. This is described in Supplementary Results.
