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

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 specifi