Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.,Cell

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Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.
Cell ( IF 45.5 ) Pub Date : 2020-09-03 , DOI: 10.1016/j.cell.2020.06.045
Ming-Huei Chen ₁ , Laura M Raffield ₂ , Abdou Mousas ₃ , Saori Sakaue ₄ , Jennifer E Huffman ₅ , Arden Moscati ₆ , Bhavi Trivedi ₇ , Tao Jiang ₈ , Parsa Akbari ₉ , Dragana Vuckovic ₁₀ , Erik L Bao ₁₁ , Xue Zhong ₁₂ , Regina Manansala ₁₃ , Véronique Laplante ₁₄ , Minhui Chen ₁₅ , Ken Sin Lo ₃ , Huijun Qian ₁₆ , Caleb A Lareau ₁₁ , Mélissa Beaudoin ₃ , Karen A Hunt ₇ , Masato Akiyama ₁₇ , Traci M Bartz ₁₈ , Yoav Ben-Shlomo ₁₉ , Andrew Beswick ₂₀ , Jette Bork-Jensen ₂₁ , Erwin P Bottinger ₂₂ , Jennifer A Brody ₂₃ , Frank J A van Rooij ₂₄ , Kumaraswamynaidu Chitrala ₂₅ , Kelly Cho ₂₆ , Hélène Choquet ₂₇ , Adolfo Correa ₂₈ , John Danesh ₂₉ , Emanuele Di Angelantonio ₃₀ , Niki Dimou ₃₁ , Jingzhong Ding ₃₂ , Paul Elliott ₃₃ , Tõnu Esko ₃₄ , Michele K Evans ₂₅ , James S Floyd ₃₅ , Linda Broer ₃₆ , Niels Grarup ₂₁ , Michael H Guo ₃₇ , Andreas Greinacher ₃₈ , Jeff Haessler ₃₉ , Torben Hansen ₂₁ , Joanna M M Howson ₄₀ , Qin Qin Huang ₁₀ , Wei Huang ₄₁ , Eric Jorgenson ₂₇ , Tim Kacprowski ₄₂ , Mika Kähönen ₄₃ , Yoichiro Kamatani ₄₄ , Masahiro Kanai ₄₅ , Savita Karthikeyan ₈ , Fotis Koskeridis ₄₆ , Leslie A Lange ₄₇ , Terho Lehtimäki ₄₈ , Markus M Lerch ₄₉ , Allan Linneberg ₅₀ , Yongmei Liu ₅₁ , Leo-Pekka Lyytikäinen ₄₈ , Ani Manichaikul ₅₂ , Hilary C Martin ₁₀ , Koichi Matsuda ₅₃ , Karen L Mohlke ₂ , Nina Mononen ₄₈ , Yoshinori Murakami ₅₄ , Girish N Nadkarni ₆ , Matthias Nauck ₅₅ , Kjell Nikus ₅₆ , Willem H Ouwehand ₅₇ , Nathan Pankratz ₅₈ , Oluf Pedersen ₂₁ , Michael Preuss ₆ , Bruce M Psaty ₅₉ , Olli T Raitakari ₆₀ , David J Roberts ₆₁ , Stephen S Rich ₅₂ , Benjamin A T Rodriguez ₁ , Jonathan D Rosen ₆₂ , Jerome I Rotter ₆₃ , Petra Schubert ₅ , Cassandra N Spracklen ₆₄ , Praveen Surendran ₆₅ , Hua Tang ₆₆ , Jean-Claude Tardif ₆₇ , Richard C Trembath ₆₈ , Mohsen Ghanbari ₆₉ , Uwe Völker ₇₀ , Henry Völzke ₇₁ , Nicholas A Watkins ₇₂ , Alan B Zonderman ₂₅ , , Peter W F Wilson ₇₃ , Yun Li ₇₄ , Adam S Butterworth ₇₅ , Jean-François Gauchat ₁₄ , Charleston W K Chiang ₇₆ , Bingshan Li ₇₇ , Ruth J F Loos ₆ , William J Astle ₇₈ , Evangelos Evangelou ₇₉ , David A van Heel ₇ , Vijay G Sankaran ₁₁ , Yukinori Okada ₈₀ , Nicole Soranzo ₈₁ , Andrew D Johnson ₁ , Alexander P Reiner ₈₂ , Paul L Auer ₁₃ , Guillaume Lettre ₆₇

Affiliation

The Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA 01702, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA 01702, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK; Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK.
Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02446, USA.
Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
Département de Pharmacologie et Physiologie, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Department of Statistics and Operation Research, University of North Carolina, Chapel Hill, NC 27599, USA.
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Department of Biostatistics, University of Washington, Seattle, WA 98101, USA.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK.
Translational Health Sciences, Musculoskeletal Research Unit, Bristol Medical School, University of Bristol, Bristol BS10 5NB, UK.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Hasso-Plattner-Institut, Universität Potsdam, Potsdam 14469, Germany.
Department of Medicine, University of Washington, Seattle, WA 98101, USA.
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam 3015, the Netherlands.
Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD 21224, USA.
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Division on Aging, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge CB2 0QQ, UK; British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge CB2 0QQ, UK; British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon 69008, France; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece.
Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Imperial Biomedical Research Centre, Imperial College London and Imperial College NHS Healthcare Trust, London SW7 2AZ, UK; Medical Research Council-Public Health England Centre for Environment, Imperial College London, London SW7 2AZ, UK; UK Dementia Research Institute, Imperial College London, London SW7 2AZ, UK; Health Data Research UK - London, London SW7 2AZ, UK.
Broad Institute of Harvard and MIT, Cambridge, MA 02446, USA.
Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA.
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam 3015, the Netherlands.
Broad Institute of Harvard and MIT, Cambridge, MA 02446, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Novo Nordisk Research Centre Oxford, Innovation Building, Old Road Campus, Oxford OX3 7FZ, UK.
Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai 201203, China.
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany; Chair of Experimental Bioinformatics, Research Group Computational Systems Medicine, Technical University of Munich, Freising-Weihenstephan 85354, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany.
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland.
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece.
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland.
Department of Internal Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg 2000, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
Duke Molecular Physiology Institute, Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27701, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
Division of Molecular Pathology, The Institute of Medical Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany; Institue of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland; Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland.
Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Department of Hematology, University of Cambridge, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
Centre for Population Health Research, University of Turku and Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20521, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland.
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK; Department of Haematology, Churchill Hospital, Oxford OX3 7LE, UK; NHS Blood and Transplant - Oxford Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA.
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, MA 01002, USA.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Montreal Heart Institute, Montreal, QC H1T 1C8, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK.
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam 3015, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran.
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany.
German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Atlanta VA Medical Center, Decatur, GA 30033, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK.
Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge CB2 0QQ, UK; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Strangeways Laboratory, Cambridge CB1 8RN, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece; Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Laboratory of Statistical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Hematology, University of Cambridge, Cambridge CB2 0PT, UK.
Department of Epidemiology, University of Washington, Seattle, WA 98109, USA.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10⁻⁹, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

中文翻译：

来自全球 5 个人群的 746,667 名个体的跨种族和血统特异性血细胞遗传学。

GWAS 识别的大多数基因座都在欧洲血统 (EUR) 人群中发现。在对 746,667 名参与者（包括 184,535 名非欧元个体）的 15 种血液学特征进行跨种族荟萃分析中，我们在 p < 5 × 10 ^-9下确定了 5,552 个特征变异关联，其中包括 71 个在欧元人群中未发现的新关联。我们还在血统特异性、非 EUR 荟萃分析中鉴定了 28 个其他新变异，包括南亚人中与体内淋巴细胞计数和体外IL-7 分泌水平相关的IL7错义变异。精细映射优先考虑注释为功能性的变体，并生成 95% 的可信集，与仅使用欧元的结果相比，使用跨种族的结果时，该集的大小要小 30%。我们探讨了多个人群中跨种族变异的临床意义和预测价值，并比较了人群之间的遗传结构和自然选择对这些血液表型的影响。总而言之，我们的血液学特征结果凸显了在遗传研究中更具有全球代表性的人群的价值。

更新日期：2020-09-03

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