Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification
Nature Genetics, vol. 55, pp. 1651–1664
Abstract
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
Authors 89
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Maryam Kavousi corresponding
Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. m.kavousi@erasmusmc.nl
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Affiliation as printed
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
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Seoul National University · University of Michigan
Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
Graduate School of Data Science, Seoul National University, Seoul, Republic of Korea
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The University of Texas Health Science Center at Houston
Affiliation as printed
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Center at Houston, Houston, TX, USA
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The University of Texas Health Science Center at Houston
Affiliation as printed
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Center at Houston, Houston, TX, USA
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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British Heart Foundation · University College London
Affiliation as printed
Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK
University College London British Heart Foundation Research Accelerator Centre, London, UK
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Leiden University Medical Center · Max Planck Institute for Biology of Ageing
Affiliation as printed
Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Max Planck Institute for Biology of Aging, Cologne, Germany
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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University of California, Los Angeles · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
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, USA
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Affiliation as printed
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
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Affiliation as printed
Population Sciences, NHLBI/NIH, Framingham, MA, USA
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Harvard University · Harvard Pilgrim Health Care
Affiliation as printed
Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA, USA
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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University of Michigan · Icelandic Heart Association
Affiliation as printed
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
Icelandic Heart Association, Kopavogur, Iceland
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University of Colorado Anschutz
Affiliation as printed
Department of Biomedical Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Department of Biostatistics, University of Washington, Seattle, WA, USA
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Leiden University Medical Center
Affiliation as printed
Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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University of California, Los Angeles · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
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, USA
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Washington University in St. Louis
Affiliation as printed
Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA
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Utrecht University · University Medical Center Utrecht · British Heart Foundation · University College London
Affiliation as printed
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK
University College London British Heart Foundation Research Accelerator Centre, London, UK
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VA Palo Alto Health Care System
Affiliation as printed
VA Palo Alto Healthcare System, Palo Alto, CA, USA
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Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Victor Chang Cardiac Research Institute · UNSW Sydney · Icahn School of Medicine at Mount Sinai
Affiliation as printed
St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia
The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Department of Biostatistical Sciences and Data Science, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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Affiliation as printed
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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University of California, Irvine
Affiliation as printed
Susan Samueli Integrative Health Institute, Department of Medicine, University of California Irvine, Irvine, CA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Radiology, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
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University of Michigan · Institute for Social Research
Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
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University of California, Los Angeles · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
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, USA
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
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Leiden University Medical Center
Affiliation as printed
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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University of Colorado Anschutz · University of Colorado Denver
Affiliation as printed
Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Denver, CO, USA
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Affiliation as printed
Icelandic Heart Association, Kopavogur, Iceland
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Affiliation as printed
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
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VA Palo Alto Health Care System · Stanford Medicine · Stanford University
Affiliation as printed
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
VA Palo Alto Healthcare System, Palo Alto, CA, USA
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences: Atherosclerosis and Ischemic syndromes, Amsterdam Infection and Immunity: Inflammatory diseases, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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The University of Texas Health Science Center at Houston
Affiliation as printed
Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA
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University of Iceland · Icelandic Heart Association
Affiliation as printed
Faculty of Medicine, School of Public Health, University of Iceland, Reykjavik, Iceland
Icelandic Heart Association, Kopavogur, Iceland
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British Heart Foundation · University College London
Affiliation as printed
Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK
University College London British Heart Foundation Research Accelerator Centre, London, UK
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Stanford Medicine · Stanford University
Affiliation as printed
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Utrecht University · University Medical Center Utrecht · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands
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Affiliation as printed
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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Tampere University · Tampere University Hospital · University of Tampere
Affiliation as printed
Department of Clinical Physiology, Tampere University Hospital and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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University of Colorado Anschutz
Affiliation as printed
Department of Biomedical Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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University of Turku · Turku University Hospital
Affiliation as printed
Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
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Affiliation as printed
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Graz, Austria
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Leiden University Medical Center
Affiliation as printed
Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Utrecht University · Erasmus MC · University Medical Center Utrecht
Affiliation as printed
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Vascular Surgery, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Affiliation as printed
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
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University of North Carolina at Chapel Hill
Affiliation as printed
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
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Affiliation as printed
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
Departments of Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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University of California, Los Angeles · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
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, USA
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Karolinska Institutet · Integrated Cardio Metabolic Centre · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
Department of Medicine, Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
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Brigham and Women's Hospital · Harvard University · VA Boston Healthcare System
Affiliation as printed
Cardiology Section, Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, MA, USA
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Clint L. Miller corresponding
Affiliation as printed
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. clintm@virginia.edu
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA. clintm@virginia.edu
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. clintm@virginia.edu
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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