Notwithstanding prior discovery of multiple genome-wide significant (GWS) loci for PAU, there are major gaps in our understanding of its genetic underpinnings. First, the estimated single-nucleotide polymorphism (SNP)-based heritability (h2) of AUD and PAU ranges from 5.6% to 10.0%, reflecting substantial ‘missing heritability’. Second, most of the available samples used in human genetic studies—including for AUD—are from individuals of EUR genetic ancestry; lack of ancestral diversity is a major problem both for understanding the genetics of these traits, and for potential applications of these genetic discoveries to global populations. Our previous study in the Million Veteran Program (MVP) analyzed AUD in multiple ancestral groups10. However, non-EUR samples (N = 72,387) were far smaller than EUR samples (N = 202,004), resulting in inadequate statistical power and unbalanced gene discovery across ancestral backgrounds.
