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Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.

Original publication

DOI

10.1038/s41588-021-00935-7

Type

Journal article

Journal

Nat genet

Publication Date

10/2021

Volume

53

Pages

1504 - 1516

Keywords

Alleles, Amino Acids, Gene Frequency, Genetic Variation, Genetics, Population, HIV Infections, HIV-1, HLA Antigens, Haplotypes, Host-Pathogen Interactions, Humans, Linkage Disequilibrium, Physical Chromosome Mapping, Reference Standards, Selection, Genetic, Viral Load