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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1038/s41588-021-00935-7

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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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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.

Original language	English
Pages (from-to)	1504-1516
Number of pages	13
Journal	Nature Genetics
Volume	53
Issue number	10
DOIs	https://doi.org/10.1038/s41588-021-00935-7
State	Published - Oct 2021

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10.1038/s41588-021-00935-7

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@article{35048083029341f59ee52c1fd526a286,

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

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 = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Yang Luo and Masahiro Kanai and Wanson Choi and Xinyi Li and Saori Sakaue and Kenichi Yamamoto and Kotaro Ogawa and Maria Gutierrez-Arcelus and Gregersen, {Peter K.} and Stuart, {Philip E.} and Elder, {James T.} and Lukas Forer and Sebastian Sch{\"o}nherr and Christian Fuchsberger and Smith, {Albert V.} and Jacques Fellay and Mary Carrington and Haas, {David W.} and Xiuqing Guo and Palmer, {Nicholette D.} and Chen, {Yii Der Ida} and Rotter, {Jerome I.} and Taylor, {Kent D.} and Rich, {Stephen S.} and Adolfo Correa and Wilson, {James G.} and Sekar Kathiresan and Cho, {Michael H.} and Andres Metspalu and Tonu Esko and Yukinori Okada and Buhm Han and Namiko Abe and Gon{\c c}alo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Kristin Ardlie and {Dan Arking}, Arking and Arnett, {Donna K.} and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and Najib Ayas and Adithya Balasubramanian and John Barnard and Kathleen Barnes and Barr, {R. Graham} and Emily Barron-Casella and Lucas Barwick and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Rebecca Beer and Amber Beitelshees and Emelia Benjamin and Takis Benos and Marcos Bezerra and Larry Bielak and Joshua Bis and Thomas Blackwell and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Jai Broome and Deborah Brown and Karen Bunting and Esteban Burchard and Carlos Bustamante and Erin Buth and Brian Cade and Jonathan Cardwell and Vincent Carey and Julie Carrier and Cara Carty and Richard Casaburi and Romero, {Juan P.Casas} and James Casella and Peter Castaldi and Mark Chaffin and Christy Chang and Chang, {Yi Cheng} and Daniel Chasman and Sameer Chavan and Chen, {Bo Juen} and Chen, {Wei Min} and Choi, {Seung Hoan} and Chuang, {Lee Ming} and Mina Chung and Chung, {Ren Hua} and Clary Clish and Suzy Comhair and Matthew Conomos and Elaine Cornell and Carolyn Crandall and James Crapo and Cupples, {L. Adrienne} and Joanne Curran and Jeffrey Curtis and Brian Custer and Coleen Damcott and Dawood Darbar and Sean David and Colleen Davis and Michelle Daya and {de Andrade}, Mariza and Fuentes, {Lisa de las} and {de Vries}, Paul and Michael DeBaun and Ranjan Deka and Dawn DeMeo and Scott Devine and Huyen Dinh and Harsha Doddapaneni and Qing Duan and Shannon Dugan-Perez and Ravi Duggirala and Durda, {Jon Peter} and Dutcher, {Susan K.} and Charles Eaton and Lynette Ekunwe and Boueiz, {Adel El} and Patrick Ellinor and Leslie Emery and Serpil Erzurum and Charles Farber and Jesse Farek and Tasha Fingerlin and Matthew Flickinger and Myriam Fornage and Nora Franceschini and Chris Frazar and Mao Fu and Fullerton, {Stephanie M.} and Lucinda Fulton and Stacey Gabriel and Weiniu Gan and Shanshan Gao and Yan Gao and Margery Gass and Heather Geiger and Bruce Gelb and Mark Geraci and Soren Germer and Robert Gerszten and Auyon Ghosh and Richard Gibbs and Chris Gignoux and Mark Gladwin and David Glahn and Stephanie Gogarten and Gong, {Da Wei} and Harald Goring and Sharon Graw and Gray, {Kathryn J.} and Daniel Grine and Colin Gross and Gu, {C. Charles} and Yue Guan and Namrata Gupta and Haas, {David M.} and Jeff Haessler and Michael Hall and Yi Han and Patrick Hanly and Daniel Harris and Hawley, {Nicola L.} and Jiang He and Ben Heavner and Susan Heckbert and Ryan Hernandez and David Herrington and Craig Hersh and Bertha Hidalgo and James Hixson and Brian Hobbs and John Hokanson and Elliott Hong and Karin Hoth and Hsiung, {Chao (Agnes)} and Jianhong Hu and Hung, {Yi Jen} and Haley Huston and Hwu, {Chii Min} and Irvin, {Marguerite Ryan} and Rebecca Jackson and Deepti Jain and Rao, {D. C.} and Sung, {Yun Ju}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = oct,

doi = "10.1038/s41588-021-00935-7",

language = "English",

volume = "53",

pages = "1504--1516",

journal = "Nature Genetics",

issn = "1061-4036",

number = "10",

}

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 - Avramopoulos, Dimitrios

AU - Ayas, Najib

AU - Balasubramanian, Adithya

AU - Barnard, John

AU - Barnes, Kathleen

AU - Barr, R. Graham

AU - Barron-Casella, Emily

AU - Barwick, Lucas

AU - Beaty, Terri

AU - Beck, Gerald

AU - Becker, Diane

AU - Becker, Lewis

AU - Beer, Rebecca

AU - Beitelshees, Amber

AU - Benjamin, Emelia

AU - Benos, Takis

AU - Bezerra, Marcos

AU - Bielak, Larry

AU - Bis, Joshua

AU - Blackwell, Thomas

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Bowler, Russell

AU - Brody, Jennifer

AU - Broeckel, Ulrich

AU - Broome, Jai

AU - Brown, Deborah

AU - Bunting, Karen

AU - Burchard, Esteban

AU - Bustamante, Carlos

AU - Buth, Erin

AU - Cade, Brian

AU - Cardwell, Jonathan

AU - Carey, Vincent

AU - Carrier, Julie

AU - Carty, Cara

AU - Casaburi, Richard

AU - Romero, Juan P.Casas

AU - Casella, James

AU - Castaldi, Peter

AU - Chaffin, Mark

AU - Chang, Christy

AU - Chang, Yi Cheng

AU - Chasman, Daniel

AU - Chavan, Sameer

AU - Chen, Bo Juen

AU - Chen, Wei Min

AU - Choi, Seung Hoan

AU - Chuang, Lee Ming

AU - Chung, Mina

AU - Chung, Ren Hua

AU - Clish, Clary

AU - Comhair, Suzy

AU - Conomos, Matthew

AU - Cornell, Elaine

AU - Crandall, Carolyn

AU - Crapo, James

AU - Cupples, L. Adrienne

AU - Curran, Joanne

AU - Curtis, Jeffrey

AU - Custer, Brian

AU - Damcott, Coleen

AU - Darbar, Dawood

AU - David, Sean

AU - Davis, Colleen

AU - Daya, Michelle

AU - de Andrade, Mariza

AU - Fuentes, Lisa de las

AU - de Vries, Paul

AU - DeBaun, Michael

AU - Deka, Ranjan

AU - DeMeo, Dawn

AU - Devine, Scott

AU - Dinh, Huyen

AU - Doddapaneni, Harsha

AU - Duan, Qing

AU - Dugan-Perez, Shannon

AU - Duggirala, Ravi

AU - Durda, Jon Peter

AU - Dutcher, Susan K.

AU - Eaton, Charles

AU - Ekunwe, Lynette

AU - Boueiz, Adel El

AU - Ellinor, Patrick

AU - Emery, Leslie

AU - Erzurum, Serpil

AU - Farber, Charles

AU - Farek, Jesse

AU - Fingerlin, Tasha

AU - Flickinger, Matthew

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Frazar, Chris

AU - Fu, Mao

AU - Fullerton, Stephanie M.

AU - Fulton, Lucinda

AU - Gabriel, Stacey

AU - Gan, Weiniu

AU - Gao, Shanshan

AU - Gao, Yan

AU - Gass, Margery

AU - Geiger, Heather

AU - Gelb, Bruce

AU - Geraci, Mark

AU - Germer, Soren

AU - Gerszten, Robert

AU - Ghosh, Auyon

AU - Gibbs, Richard

AU - Gignoux, Chris

AU - Gladwin, Mark

AU - Glahn, David

AU - Gogarten, Stephanie

AU - Gong, Da Wei

AU - Goring, Harald

AU - Graw, Sharon

AU - Gray, Kathryn J.

AU - Grine, Daniel

AU - Gross, Colin

AU - Gu, C. Charles

AU - Guan, Yue

AU - Gupta, Namrata

AU - Haas, David M.

AU - Haessler, Jeff

AU - Hall, Michael

AU - Han, Yi

AU - Hanly, Patrick

AU - Harris, Daniel

AU - Hawley, Nicola L.

AU - He, Jiang

AU - Heavner, Ben

AU - Heckbert, Susan

AU - Hernandez, Ryan

AU - Herrington, David

AU - Hersh, Craig

AU - Hidalgo, Bertha

AU - Hixson, James

AU - Hobbs, Brian

AU - Hokanson, John

AU - Hong, Elliott

AU - Hoth, Karin

AU - Hsiung, Chao (Agnes)

AU - Hu, Jianhong

AU - Hung, Yi Jen

AU - Huston, Haley

AU - Hwu, Chii Min

AU - Irvin, Marguerite Ryan

AU - Jackson, Rebecca

AU - Jain, Deepti

AU - Rao, D. C.

AU - Sung, Yun Ju

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 - http://www.scopus.com/inward/record.url?scp=85116750590&partnerID=8YFLogxK

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 -

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

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