Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

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

10/07/2021

Pubmed ID

34611364

Pubmed Central ID

PMC8959399

DOI

10.1038/s41588-021-00935-7

Scopus ID

2-s2.0-85116750590 (requires institutional sign-in at Scopus site)   49 Citations

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.

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 S

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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