Shared trans-ancestry architecture of HLA-mediated disease risk in the All of Us Research Program

Abstract

The human leukocyte antigen (HLA) region is the strongest genetic contributor to many immune-mediated diseases, yet whether HLA architecture is shared across ancestries remains unclear. We analyzed high-resolution HLA variation in 390,823 participants from the All of Us Research Program spanning six genetic ancestry groups, including 262,915 with linked electronic health records. Using whole-genome sequencing and graph-based inference, we genotyped 20 HLA genes at G-group resolution and identified 4,780 distinct alleles. Analyses accounting for disparate sample sizes demonstrated that ancestry-private allelic variation reflected unequal discovery depth rather than ancestry-population specificity. A meta-analysis of ancestry-stratified phenome-wide association analyses with 363 HLA alleles with frequency > 0.001 and 3,430 clinical phenotypes identified 1,461 significant HLA-phenotype associations (FDR < 0.05). Although many associations reached significance in only one ancestry group, effect directions were largely concordant, highlighting differences in allele frequency, linkage disequilibrium, and statistical power among ancestry groups. Stepwise conditional modeling demonstrated that common complex trait variation could be concurrently explained by five to seven independent HLA allele signals. These findings demonstrate that a multi-ancestry, phenome-wide study can distinguish true biological heterogeneity from sampling-driven detectability differences in HLA.