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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Luo, Y; Kanai, M; Choi, W; Li, X; Sakaue, S; Yamamoto, K; Ogawa, K; Gutierrez-Arcelus, M; Gregersen, PK; Stuart, PE; Elder, JT; Forer, L; Schönherr, S; Fuchsberger, C; Smith, AV; Fellay, J; Carrington, M; Haas, DW; Guo, X; Palmer, ND; Chen, Y-DI; Rotter, JI; Taylor, KD; Rich, SS; Correa, A; Wilson, JG; Kathiresan, S; Cho, MH; Metspalu, A; Esko, T; Okada, Y; Han, B; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, ; McLaren, PJ; Raychaudhuri, S

Published Date

  • October 2021

Published In

Volume / Issue

  • 53 / 10

Start / End Page

  • 1504 - 1516

PubMed ID

  • 34611364

Pubmed Central ID

  • PMC8959399

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-021-00935-7

Language

  • eng

Conference Location

  • United States