Lead SNP ADH1B*rs1229984 is a long-established risk locus from the pre-GWAS era that has been strongly confirmed by GWAS (2, 6). To identify rs1229984 as the lead variant, we needed to address a data-cleaning dilemma, as this variant was initially excluded from analysis on HWE criteria. Knowing the importance of the variant, we investigated the situation further, and discovered two subpopulations within the EUR, one with higher rs1229984 MAF (that clusters with Ashkenazi Jews(41)), and another much larger subpopulation with lower MAF. HWE criteria for this key variant were met within both of these individual subpopulations. In the initial quality control investigation, the violation of HWE expectations was, we conclude, attributable to this demonstrable violation of the random mating assumption (and not to a problem with data quality). We recommend that studies that may have excluded ADH1B*rs1229984 on HWE grounds examine this same issue.
