A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response

Nat Genet. 2021 Oct;53(10):1504-1516. doi: 10.1038/s41588-021-00935-7. Epub 2021 Oct 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Amino Acids
  • HLA Antigens

Grant support