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

Academic Article

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.
  • Published In

  • Nature Genetics  Journal
  • Digital Object Identifier (doi)

    Author List

  • Luo Y; Kanai M; Choi W; Li X; Sakaue S; Yamamoto K; Ogawa K; Gutierrez-Arcelus M; Gregersen PK; Stuart PE
  • Start Page

  • 1504
  • End Page

  • 1516
  • Volume

  • 53
  • Issue

  • 10