Journal article
A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
Nature genetics, Vol.53(10), pp.1504-1516
10/01/2021
DOI: 10.1038/s41588-021-00935-7
PMCID: PMC8959399
PMID: 34611364
Abstract
A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of HLA alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.
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.
Details
- Title: Subtitle
- A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
- Creators
- Yang Luo - Brigham and Women's HospitalMasahiro Kanai - Harvard UniversityWanson Choi - Seoul National UniversityXinyi Li - University of ChicagoSaori Sakaue - Brigham and Women's HospitalKenichi Yamamoto - The University of OsakaKotaro Ogawa - The University of OsakaMaria Gutierrez-Arcelus - Brigham and Women's HospitalPeter K. Gregersen - Feinstein Institute for Medical ResearchPhilip E. Stuart - University of MichiganJames T. Elder - Veterans Health AdministrationLukas Forer - Innsbruck Medical UniversitySebastian Schoenherr - Med Univ Innsbruck, Inst Genet Epidmiol, Dept Genet & Pharmacol, Innsbruck, AustriaChristian Fuchsberger - Innsbruck Medical UniversityAlbert V. Smith - University of MichiganMary Carrington - Ragon Institute of MGH, MIT and HarvardDavid W. Haas - Meharry Medical CollegeXiuqing Guo - The Lundquist InstituteNicholette D. Palmer - Wake Forest UniversityYii-Der Ida Chen - The Lundquist InstituteJerome I. Rotter - The Lundquist InstituteKent D. Taylor - The Lundquist InstituteStephen S. Rich - University of VirginiaAdolfo Correa - University of Mississippi Medical CenterJames G. Wilson - University of Mississippi Medical CenterSekar Kathiresan - Broad InstituteMichael H. Cho - Brigham and Women's HospitalAndres Metspalu - University of TartuTonu Esko - Broad InstituteYukinori Okada - The University of OsakaBuhm Han - Seoul National UniversityPaul J. McLaren - University of ManitobaSoumya Raychaudhuri - Brigham and Women's HospitalNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Contributors
- Karin Hoth (Contributor) - University of Iowa, PsychiatryRobert Wallace (Contributor) - University of Iowa, Internal Medicine
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.53(10), pp.1504-1516
- DOI
- 10.1038/s41588-021-00935-7
- PMID
- 34611364
- PMCID
- PMC8959399
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 30
- Grant note
- R01 AR063611; R01 AR042742; R01 AR050511 / NIAMS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) HHSN268201800013I / NIMHD NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Minority Health & Health Disparities (NIMHD) HHSN261201800010I; HHSN261201800012I; HHSN261201800014I; HHSN261200800001E / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01 NS058700 / NINDS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) UL1 TR001420; UL1 TR001079; UL1 TR000040 / NCATS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) UL1 RR033176 / NCRR NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R01 DK071891 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) UM1 AI068634; U19 AI111224; UM1 AI068636; UM1 AI106701 / NIAID NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) K01 AG059898; R01 AG058921 / NIA NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) F32 HL085989; R01 HL071250; R01 HL117626; HHSN268201000001I; HHSN268201100011I; R01 HL120393; R01 HL071259; HHSN268201800015I; R01 HL071051; R01 HL071205; U01 HL089856; R01 HL071258; HHSN268201500003I; U01 HL120393; U01 HL089897 / NHLBI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 10/01/2021
- Academic Unit
- Psychiatry; Epidemiology; Iowa Neuroscience Institute; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984293654802771
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