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

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A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
Nature Genetics ( IF 31.7 ) Pub Date : 2021-10-05 , DOI: 10.1038/s41588-021-00935-7
Yang Luo _{1,

2,

3,

4,

5} , Masahiro Kanai _{4,

5,

6,

7,

8} , Wanson Choi ₉ , Xinyi Li ₁₀ , Saori Sakaue _{1,

2,

3,

4,

5} , Kenichi Yamamoto _{8,

11} , Kotaro Ogawa _{8,

12} , Maria Gutierrez-Arcelus _{1,

2,

3,

4,

5} , Peter K Gregersen ₁₃ , Philip E Stuart ₁₄ , James T Elder _{14,

15} , Lukas Forer ₁₆ , Sebastian Schönherr ₁₆ , Christian Fuchsberger _{16,

17,

18,

19} , Albert V Smith _{17,

18} , Jacques Fellay _{20,

21} , Mary Carrington _{22,

23} , David W Haas _{24,

25} , Xiuqing Guo ₂₆ , Nicholette D Palmer ₂₇ , Yii-Der Ida Chen ₂₆ , Jerome I Rotter ₂₆ , Kent D Taylor ₂₆ , Stephen S Rich ₂₈ , Adolfo Correa ₂₉ , James G Wilson ₃₀ , Sekar Kathiresan _{5,

31,

32} , Michael H Cho ₃₃ , Andres Metspalu ₃₄ , Tonu Esko _{5,

34} , Yukinori Okada _{8,

35} , Buhm Han _{9,

36} , , Paul J McLaren _{37,

38} , Soumya Raychaudhuri _{1,

2,

3,

4,

5,

39}

Affiliation

Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA.
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research,North Short LIJ Health System, Manhasset, NY, USA.
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA.
Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Institute for Biomedicine, Eurac Research, Bolzano, Italy.
Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
School of Life Sciences, EPFL, Lausanne, Switzerland.
Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
Vanderbilt University Medical Center, Nashville, TN, USA.
Meharry Medical College, Nashville, TN, USA.
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.
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, South Korea.
J.C. Wilt Infectious Diseases Research Centre, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
Centre for Genetics and Genomics Versus Arthritis, University of Manchester, Manchester, UK.

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.

中文翻译：

捕捉全球人口多样性的高分辨率 HLA 参考面板可实现 HIV 宿主反应的多祖先精细绘图

对可能的因果变异进行精细映射可能在多祖先群体中更有效，特别是在具有群体特异性结构的 MHC 中。为了进行此类研究，我们基于全基因组序列构建了一个涵盖全球五个人群的大型 ( n = 21,546) HLA 参考组。尽管存在特定于人群的长程单倍型，但我们在 G 组分辨率下证明了准确的插补（在混合非洲 (AA)、东亚 (EAS)、欧洲 (EUR) 和拉丁裔中分别为 94.2%、93.7%、97.8% 和 93.7%（ LAT）人口）。将 HLA 推算应用于三个人群（EUR、AA 和 LAT）中 HIV-1 病毒载量的全基因组关联研究数据，我们消除了先前报道的人群特异性 HIV 研究中关联的影响，并在 HLA 的第 156 位发现了一种新的关联-B。我们精确定位了 MHC 与 HLA-B 肽结合沟内三个连续口袋（C、B 和 D）的三个氨基酸位置（97、67 和 156）的关联，解释了 12.9% 的性状变异。

更新日期：2021-10-05

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