Large-scale admixture mapping in the All of Us Research Program improves the characterization of cross-population phenotypic differences.

Admixed individuals have been understudied in medical research largely due to their complex genetic ancestries. However, the consideration of admixture can identify ancestry-enriched genetic associations, delineating genetic underpinnings of cross-population phenotypic variation. Here, we performed admixture mapping in individuals with inferred admixture from African and European populations (N = 48,921). Across 22 traits, we identified 71 ancestry-trait associations, including loci where ancestral haplotypes explained phenotypic variation yet were missed by single-variant association testing due to their stricter multiple testing burden. One such locus where inferred local AFR ancestries are associated with increased hemoglobin A1c (HbA1c) was 12q14.3, highlighting its potential role in explaining differences between populations. Together, our results expand upon the phenotypic differences between populations and characterize loci where genetic ancestries play a critical role in the architecture of disease.