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
Date
10/07/2021Pubmed ID
34611364Pubmed Central ID
PMC8959399DOI
10.1038/s41588-021-00935-7Scopus ID
2-s2.0-85116750590 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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.
Author List
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 YI, 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 SAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAmino 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