TY - JOUR
T1 - A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Luo, Yang
AU - Kanai, Masahiro
AU - Choi, Wanson
AU - Li, Xinyi
AU - Sakaue, Saori
AU - Yamamoto, Kenichi
AU - Ogawa, Kotaro
AU - Gutierrez-Arcelus, Maria
AU - Gregersen, Peter K.
AU - Stuart, Philip E.
AU - Elder, James T.
AU - Forer, Lukas
AU - Schönherr, Sebastian
AU - Fuchsberger, Christian
AU - Smith, Albert V.
AU - Fellay, Jacques
AU - Carrington, Mary
AU - Haas, David W.
AU - Guo, Xiuqing
AU - Palmer, Nicholette D.
AU - Chen, Yii Der Ida
AU - Rotter, Jerome I.
AU - Taylor, Kent D.
AU - Rich, Stephen S.
AU - Correa, Adolfo
AU - Wilson, James G.
AU - Kathiresan, Sekar
AU - Cho, Michael H.
AU - Metspalu, Andres
AU - Esko, Tonu
AU - Okada, Yukinori
AU - Han, Buhm
AU - Abe, Namiko
AU - Abecasis, Gonçalo
AU - Aguet, Francois
AU - Albert, Christine
AU - Almasy, Laura
AU - Alonso, Alvaro
AU - Ament, Seth
AU - Anderson, Peter
AU - Anugu, Pramod
AU - Applebaum-Bowden, Deborah
AU - Ardlie, Kristin
AU - Dan Arking, Arking
AU - Arnett, Donna K.
AU - Ashley-Koch, Allison
AU - Aslibekyan, Stella
AU - Assimes, Tim
AU - Auer, Paul
AU - Ochs-Balcom, Heather
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85116750590
U2 - 10.1038/s41588-021-00935-7
DO - 10.1038/s41588-021-00935-7
M3 - Article
C2 - 34611364
AN - SCOPUS:85116750590
SN - 1061-4036
VL - 53
SP - 1504
EP - 1516
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -