A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
bioRxiv (Cold Spring Harbor Laboratory), vol. 109, pp. 1366–1387
Abstract
Abstract A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1 , show convergent evidence across functional datasets supporting their roles in lipid biology.
Authors 99
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Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 904, USA
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Stanford Medicine · Stanford University
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Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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University of Michigan · Michigan Medicine
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Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA
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Queen Mary University of London · William Harvey Research Institute
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William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse square, EC1M 6BQ, UK
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Affiliation as printed
Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA 02118, USA
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University of Michigan · Michigan Medicine
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Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA
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Affiliation as printed
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 904, USA
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VA Palo Alto Health Care System · Stanford Medicine · Stanford University
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Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
VA Palo Alto Health Care Systems, Palo Alto, California, USA
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Affiliation as printed
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Affiliation as printed
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 904, USA
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Queen Mary University of London · William Harvey Research Institute
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William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse square, EC1M 6BQ, UK
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Broad Institute · Boston Children's Hospital
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Endocrinology, Boston Childrens Hospital, Boston 02115 MA, USA
Medical and Population Genetics, Broad Institute, 75 Ames street, Cambridge, MA 02142, USA
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Affiliation as printed
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
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Washington University in St. Louis
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McDonnell Genome Institute and Department of Medicine, Washington University, St. Louis, MO, 63108, USA
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Queen Mary University of London · William Harvey Research Institute
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William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse square, EC1M 6BQ, UK
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Affiliation as printed
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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Affiliation as printed
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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Queen Mary University of London · William Harvey Research Institute
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Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ UK
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Emory University · Atlanta VA Health Care System
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Atlanta VA Health Care System, Decatur, GA, USA
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA
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Broad Institute · University of Florida Health · University of Florida · Malcom Randall VA Medical Center
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Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL, USA
Malcolm Randall VA Medical Center, Gainesville, FL, USA
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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VA Palo Alto Health Care System
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VA Palo Alto Health Care Systems, Palo Alto, California, USA
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Emory University · Atlanta VA Health Care System
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Atlanta VA Health Care System, Decatur, GA, USA
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA
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University of Michigan · Michigan Medicine
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Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, 48109, USA
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deCODE genetics/Amgen, Inc. Sturlugata 8, Reykjavik, 102, Iceland
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deCODE genetics/Amgen, Inc. Sturlugata 8, Reykjavik, 102, Iceland
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deCODE Genetics (Iceland) · University of Iceland
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School of Engineering and Natural Sciences, University of Iceland, Sæmundargötu 2, Reykjavik, 102, Iceland
deCODE genetics/Amgen, Inc. Sturlugata 8, Reykjavik, 102, Iceland
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deCODE genetics/Amgen, Inc. Sturlugata 8, Reykjavik, 102, Iceland
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National University Hospital of Iceland
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Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik, 101, Iceland
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Korea National Institute of Health
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Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, South Korea
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Korea National Institute of Health
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Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, South Korea
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Kyushu University · RIKEN Center for Integrative Medical Sciences
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Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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RIKEN Center for Integrative Medical Sciences · The University of Tokyo · The University of Osaka
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Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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RIKEN Center for Integrative Medical Sciences
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Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Broad Institute · Harvard University · RIKEN Center for Integrative Medical Sciences
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Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
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Broad Institute · University of Michigan · Massachusetts General Hospital
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Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Norwegian University of Science and Technology · University of Bristol · St Olav's University Hospital · MRC Integrative Epidemiology Unit
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Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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University of Oslo · Norwegian University of Science and Technology · University of Bristol · MRC Integrative Epidemiology Unit
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Division of Medicine and Laboratory Sciences, University of Oslo, Norway
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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University of Helsinki · Finnish Institute for Health and Welfare · Institute for Molecular Medicine Finland · HiLIFE – Elämäntieteiden Instituutti
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Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 8, 00014 Helsinki, Finland
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Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
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Department of Medicine (Medical Genetics), University of Washington, WA, USA
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Cincinnati Children's Hospital Medical Center
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Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, OH, USA
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Vanderbilt University · Vanderbilt University Medical Center
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Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA
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Tohoku University · Tohoku Medical Megabank Organization
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Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
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Tohoku University · Tohoku Medical Megabank Organization
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Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK
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Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Queen Mary University of London · Blizard Institute
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Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle WA 9810, USA
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Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
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Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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Western General Hospital · Institute of Genetics and Cancer · University of Edinburgh
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Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
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Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
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University of Oxford · MRC Population Health Research Unit
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Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
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Center for Non-Communicable Diseases
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Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan
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Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha, Qatar
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University of Michigan · Institute for Social Research
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Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
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Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
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University of Michigan · Institute for Social Research
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Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
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Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
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Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
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University of North Carolina at Chapel Hill
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Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC USA
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University of the Witwatersrand
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Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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University of the Witwatersrand
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Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Centre for Human Genetics · University of Oxford
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Wellcome Centre for Human Genetics, University of Oxford, UK
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Imperial College Healthcare NHS Trust · Ealing Hospital · London North West Healthcare NHS Trust · Imperial College London
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Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, Middlesex UB1 3HW, UK
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK
Imperial College Healthcare NHS Trust, London W12 0HS, UK
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Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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Uppsala University · Science for Life Laboratory
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Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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University of Cambridge · MRC Epidemiology Unit
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MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK
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Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK
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Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Korea National Institute of Health
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Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, South Korea
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Korea National Institute of Health
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Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungcheongbuk-do, South Korea
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Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands
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Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA 02118, USA
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Amsterdam University Medical Centers · Vrije Universiteit Amsterdam
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Amsterdam Public Health Research Institute, Amsterdam UMC, the Netherlands
Department of Biological Psychology, Vrije Universiteit Amsterdam, The Netherlands
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Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK
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Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK
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Nanjing University of Chinese Medicine · Helmholtz Munich
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Department of Clinical Acupuncture and Moxibustion, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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University of Bristol · MRC Integrative Epidemiology Unit
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Bristol Dental School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, United Kingdom
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University of Bristol · MRC Integrative Epidemiology Unit
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MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield Grove, Bristol, BS8 2BN, United Kingdom
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National University of Singapore · National University Health System
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Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 117549, Singapore
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University of Copenhagen · Frederiksberg Hospital · Bispebjerg Hospital · Center for Clinical Research and Prevention
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Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Frederiksberg Hospital · Bispebjerg Hospital · Center for Clinical Research and Prevention
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Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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The Lundquist Institute · Harbor–UCLA Medical Center
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The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovations (Formerly LABioMed) at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
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Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903 USA
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Taichung Veterans General Hospital
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Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
No. 1650, Sec. 4, Taiwan Boulevard, Taichung City 40705, Taiwan
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National Health Research Institutes
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Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC
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Queen Mary University of London · William Harvey Research Institute
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NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
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Queen Mary University of London · William Harvey Research Institute
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William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Frederiksberg Hospital · Bispebjerg Hospital · Center for Clinical Research and Prevention
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Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Centre for Human Genetics · John Radcliffe Hospital · University of Oxford
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Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford. UK. OX3 9DU
Wellcome Centre for Human Genetics, University of Oxford, Oxford. UK. OX3 7BN
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Karolinska University Hospital · Karolinska Institutet · Institut de Recerca Sant Pau
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Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
Unit of Genomics of Complex Diseases. Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain