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

Yang Luo; Masahiro Kanai; Wanson Choi; Xinyi Li; Saori Sakaue; Kenichi Yamamoto; Kotaro Ogawa; Maria Gutierrez-Arcelus; Peter K Gregersen; Philip E Stuart; James T Elder; Lukas Forer; Sebastian Schönherr; Christian Fuchsberger; Albert V Smith; Jacques Fellay; Mary Carrington; David W Haas; Xiuqing Guo; Nicholette D Palmer; Yii-Der Ida Chen; Jerome I Rotter; Kent D Taylor; Stephen S Rich; Adolfo Correa; James G Wilson; Sekar Kathiresan; Michael H Cho; Andres Metspalu; Tonu Esko; Yukinori Okada; Buhm Han; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Paul J McLaren; Soumya Raychaudhuri

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

Nat Genet. 2021 Oct;53(10):1504-1516. doi: 10.1038/s41588-021-00935-7. Epub 2021 Oct 5.

Authors

Yang Luo^{1

2

3

4

5}, Masahiro Kanai^{6

7

8

9

10}, Wanson Choi¹¹, Xinyi Li¹², Saori Sakaue^{13

14

15

6

7}, Kenichi Yamamoto^{10

16}, Kotaro Ogawa^{10

17}, Maria Gutierrez-Arcelus^{13

14

15

6

7}, Peter K Gregersen¹⁸, Philip E Stuart¹⁹, James T Elder^{19

20}, Lukas Forer²¹, Sebastian Schönherr²¹, Christian Fuchsberger^{21

22

23

24}, Albert V Smith^{22

23}, Jacques Fellay^{25

26}, Mary Carrington^{27

28}, David W Haas^{29

30}, Xiuqing Guo³¹, Nicholette D Palmer³², Yii-Der Ida Chen³¹, Jerome I Rotter³¹, Kent D Taylor³¹, Stephen S Rich³³, Adolfo Correa³⁴, James G Wilson³⁵, Sekar Kathiresan^{7

36

37}, Michael H Cho³⁸, Andres Metspalu³⁹, Tonu Esko^{7

39}, Yukinori Okada^{10

40}, Buhm Han^{11

41}; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Paul J McLaren^{42

43}, Soumya Raychaudhuri^{44

45

46

47

48

49}

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium:
Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, Cara Carty, Richard Casaburi, Juan P Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J Gray, Daniel Grine, Colin Gross, C Charles Gu, Yue Guan, Namrata Gupta, David M Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J F Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, Braxton D Mitchell, Matt Moll, Zeineen Momin, May E Montasser, Courtney Montgomery, Donna Muzny, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T Paik, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S Ramachandran, D C Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi'a Sefuiva Reupena, Ken Rice, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E Weeks, Joshua Weinstock, Bruce Weir, Scott T Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
² Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
³ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected].
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁶ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁹ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹¹ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
¹² Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA.
¹³ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
¹⁷ Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
¹⁸ The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research,North Short LIJ Health System, Manhasset, NY, USA.
¹⁹ Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA.
²¹ Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
²² Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²³ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁴ Institute for Biomedicine, Eurac Research, Bolzano, Italy.
²⁵ Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁶ School of Life Sciences, EPFL, Lausanne, Switzerland.
²⁷ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
²⁸ Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
²⁹ Vanderbilt University Medical Center, Nashville, TN, USA.
³⁰ Meharry Medical College, Nashville, TN, USA.
³¹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³² Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
³⁴ Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
³⁵ Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
³⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁷ Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁸ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁹ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴⁰ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
⁴¹ Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, South Korea.
⁴² J.C. Wilt Infectious Diseases Research Centre, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
⁴³ Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
⁴⁴ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴⁵ Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴⁶ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁴⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected].
⁴⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁴⁹ Centre for Genetics and Genomics Versus Arthritis, University of Manchester, Manchester, UK. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acids / genetics
Gene Frequency / genetics
Genetic Variation*
Genetics, Population*
HIV Infections / genetics*
HIV-1 / genetics
HLA Antigens / genetics*
Haplotypes / genetics
Host-Pathogen Interactions / genetics*
Humans
Linkage Disequilibrium / genetics
Physical Chromosome Mapping*
Reference Standards
Selection, Genetic
Viral Load

Substances

Amino Acids
HLA Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding