Large-Scale Gene-Smoking Interactions and Fine Mapping Study Identifies Multiple Novel Blood Pressure Loci in over 1 Million Individuals
Abstract
Abstract Cigarette smoking influences blood pressure (BP) levels. Studying and accounting for potential gene-smoking interactions can help discover novel loci and provide insights into biological pathways for smoking-associated BP regulation. We conducted a genome-wide association meta-analysis involving 1,188,241 individuals from 66 studies in five ancestry groups, analyzing systolic BP, diastolic BP, and pulse pressure while considering interactions between genetic variants and three smoking exposures: smoking status, cigarettes per day, and pack years. These analyses identified twelve novel loci for BP at genome-wide significance ( P < 5 × 10 −9 ), and highlighted biological processes including tight junction integrity, mitochondrial health, vascular relaxation, and endothelial function. In smoking status-stratified analyses, smoking modifies the genetic effect of six variants on BP. To prioritize likely causal, we developed and applied SuSiEgxe, a fine-mapping method based on a two-degree-of-freedom joint test using gene-environment interaction summary statistics. Fine-mapped loci uncovered immune-related pathway for smoking-associated BP regulation.
Authors 96
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The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
The University of Texas Health Science Center at Houston
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The University of Texas Health Science Center at Houston
Affiliation as printed
Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
The University of Texas Health Science Center at Houston
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National Institutes of Health · National Human Genome Research Institute
Affiliation as printed
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA
National Human Genome Research Institute
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Affiliation as printed
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
University of Regensburg
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Health Campus the Hague/Public Health and Primary Care, Leiden University Medical Center, the Hague, the Netherlands
Leiden University Medical Center
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Affiliation as printed
Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA
Brigham and Women's Hospital
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The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
The University of Texas Health Science Center at Houston
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Seoul National University · Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases · The University of Texas Health Science Center at Houston
Affiliation as printed
Graduate School of Data Science, Seoul National University, South Korea
McGovern Medical School, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
The University of Texas Health Science Center at Houston
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Washington University in St. Louis
Affiliation as printed
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA
Washington University School of Medicine
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, South Holland, the Netherlands
Leiden University Medical Center
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA
Department of Medicine, Harvard Medical School, Boston, MA, USA
Massachusetts General Hospital
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University of Maryland, Baltimore · University of Maryland School of Medicine
Affiliation as printed
University of Maryland School of Medicine
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University of Michigan · Institute for Social Research
Affiliation as printed
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
University of Groningen, University Medical Center Groningen
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Affiliation as printed
Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA
University of Washington
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University of Leicester · University Hospitals of Leicester NHS Trust
Affiliation as printed
Genetic Epidemiology Group, Department of Population Health Sciences, University of Leicester, Leicester, UK
University Hospitals of Leicester NHS Trust, Leicester, UK
University of Leicester
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University of the Witwatersrand · MRC Unit the Gambia · Institut de Recherche en Sciences de la Santé · Clinical Research Unit Nanoro
Affiliation as printed
Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, Ouagadougou, Kadiogo, Burkina Faso
MRC Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, The Gambia
Sydney Brenner Institute for Molecular Bioscience (SBIMB), University of the Witwatersrand, Johannesburg, Gauteng, South Africa
Clinical Research Unit of Nanoro
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Affiliation as printed
Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Newcastle University
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Affiliation as printed
Unit of Genomics of Complex Disease, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Catalonia, Spain
Institut de Recerca Sant Pau (IR SANT PAU)
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Wake Forest University School of Medicine
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Washington University in St. Louis
Affiliation as printed
Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, St. Louis, MO, USA
Washington University in St. Louis
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University of North Carolina at Chapel Hill
Affiliation as printed
Department of Biostatistics, University of North Carolina at Chapel Hill, NC
University of North Carolina at Chapel Hill
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Washington University in St. Louis
Affiliation as printed
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA
Washington University School of Medicine
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Vanderbilt University · VA Tennessee Valley Healthcare System · Vanderbilt University Medical Center
Affiliation as printed
Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA
VA Tennessee Valley Healthcare System (626), Nashville, TN, USA
Vanderbilt University Medical Center
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Affiliation as printed
Division of Preventive Medicine, Medicine, Brigham and Women's Hospital, Boston, MA, USA
Brigham and Women's Hospital
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University of Iceland · Icelandic Heart Association
Affiliation as printed
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Icelandic Heart Association, Kopavogur, Iceland
Icelandic Heart Association
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University of California, Los Angeles · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
Genomic Outcomes, Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
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Affiliation as printed
Lothian Birth Cohorts, Psychology, The University of Edinburgh, Edinburgh, UK
The University of Edinburgh
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The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
The University of Texas Health Science Center at Houston
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Affiliation as printed
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
University of Regensburg
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RIKEN Center for Integrative Medical Sciences
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Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
RIKEN Center for Integrative Medical Sciences
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Affiliation as printed
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
Medical University of Graz
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Wake Forest University Health Sciences · Wake Forest University
Affiliation as printed
Division of Public Health Sciences, Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Wake Forest University School of Medicine
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Affiliation as printed
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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Affiliation as printed
Graduate School of Data Science, Seoul National University, South Korea
Seoul National University
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University of Mississippi Medical Center
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University of Mississippi Medical Center, Jackson, MS, USA
University of Mississippi Medical Center
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Tampere University · Fimlab (Finland) · University of Tampere
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Department of Clinical Chemistry, Tampere University, Tampere, Finland
Fimlab Laboratories
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Inserm · Université de Lille · Institut Pasteur de Lille · Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement
Affiliation as printed
Lille University; Lille University Hospital; INSERM U1167 - RID-AGE; Institut Pasteur de Lille, University of Lille, Inserm, Institut Pasteur de Lille, Lille, France
University of Lille, Inserm, Institut Pasteur de Lille
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Inserm · Université de Lille · Institut Pasteur de Lille · Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement
Affiliation as printed
Lille University; Lille University Hospital; INSERM U1167 - RID-AGE; Institut Pasteur de Lille, University of Lille, Inserm, Institut Pasteur de Lille, Lille, France
University of Lille, Inserm, Institut Pasteur de Lille
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Affiliation as printed
Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Nagoya University Graduate School of Medicine
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Affiliation as printed
Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
University of Trieste
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Institute of Genetics and Biophysics
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Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, Naples, Italy
Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR
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IRCCS Materno Infantile Burlo Garofolo
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Institute for Maternal and Child Health, I.R.C.C.S. "Burlo Garofolo", Trieste, Italy
Burlo Garofalo Pediatric Institute: IRCCS materno infantile Burlo Garofolo
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University of Maryland, Baltimore
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Graduate Program in Life Sciences, University of Maryland, Baltimore, Baltimore, MD, USA
University of Maryland, Baltimore
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Affiliation as printed
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
Kuopio Research Institute of Exercise Medicine
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Queen Mary University of London · Barts Health NHS Trust · William Harvey Research Institute
Affiliation as printed
Barts Heart Centre, Barts Health NHS Trust, London, UK
William Harvey Research Institute, Centre for Pharmacology and Precision Medicine, Queen Mary University of London, London, UK
Queen Mary University of London
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University of Trieste · IRCCS Materno Infantile Burlo Garofolo
Affiliation as printed
Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
Institute for Maternal and Child Health, I.R.C.C.S. "Burlo Garofolo", Trieste, Italy
University of Trieste
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National Institutes of Health · National Institute on Aging
Affiliation as printed
National Institute on Aging, Bethesda, MD, USA
National Institute on Aging
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Affiliation as printed
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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National Center for Global Health and Medicine
Affiliation as printed
Department of Bioinformatics, National Institute of Global Health and Medicine, Japan Institute for Health Security, Shinjuku-ku, Tokyo, Japan
Japan Institute for Health Security
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National University of Singapore · National University Health System
Affiliation as printed
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore, Singapore
National University of Singapore and National University Health System
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Affiliation as printed
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Boston University School of Public Health
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Affiliation as printed
Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec City, Quebec, Canada
Laval University
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
Leiden University Medical Center
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
University of Groningen, University Medical Center Groningen
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University of North Carolina at Chapel Hill · Beijing Tongren Hospital · Capital Medical University
Affiliation as printed
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
Gillings School of Global Public Health, Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory
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University of Alabama at Birmingham · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Icahn School of Medicine at Mount Sinai
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University of North Carolina at Chapel Hill · Beijing Tongren Hospital · Capital Medical University
Affiliation as printed
Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
Gillings School of Global Public Health, Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
The University of North Carolina at Chapel Hill
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University of Michigan · Institute for Social Research
Affiliation as printed
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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Universitätsmedizin Greifswald · Universität Greifswald · German Centre for Cardiovascular Research
Affiliation as printed
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
University Medicine Greifswald
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Affiliation as printed
Faculty of Medicine, University of Kelaniya, Kelaniya, Ragama, Sri Lanka
University of Kelaniya
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Affiliation as printed
School of Public Health and Preventive Medicine, Monash University, Victoria 3004 Australia
Monash University
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Vanderbilt University Medical Center
Affiliation as printed
Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Vanderbilt University Medical Center
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University of Mississippi Medical Center
Affiliation as printed
Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA
University of Mississippi Medical Center
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University of Mississippi Medical Center
Affiliation as printed
Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA
University of Mississippi Medical Center
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University Hospital Regensburg
Affiliation as printed
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
University Hospital Regensburg
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Columbia University Irving Medical Center
Affiliation as printed
General Medicine, Medicine, Columbia University Medical Center, New York, NY, USA
Columbia University Medical Center
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Vanderbilt University · VA Tennessee Valley Healthcare System · Nashville VA Medical Center · Vanderbilt University Medical Center
Affiliation as printed
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Tennessee Valley Healthcare System, Nashville VA Medical Center, Nashville, TN, USA
Nashville VA Medical Center
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Baylor College of Medicine · The University of Texas Health Science Center at Houston
Affiliation as printed
Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
The University of Texas Health Science Center at Houston
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Vanderbilt University Medical Center
Affiliation as printed
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Vanderbilt University Medical Center
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Affiliation as printed
Section of Genomic Pediatrics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
Medical College of Wisconsin
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University of Leicester · University Hospitals of Leicester NHS Trust
Affiliation as printed
Department of Respiratory Sciences, University of Leicester, Leicester, UK
University Hospitals of Leicester NHS Trust, Leicester, UK
University of Leicester
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Brigham and Women's Hospital · Harvard University
Affiliation as printed
Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA
Division of Sleep and Circadian Disorders, Department of Medicine, Harvard Medical School, Boston, MA, USA
Brigham and Women's Hospital
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Affiliation as printed
Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
University of Trieste
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Affiliation as printed
Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Johns Hopkins University
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Singapore National Eye Center · Singapore Eye Research Institute
Affiliation as printed
Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore, Singapore
Singapore National Eye Center
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National Institutes of Health · National Human Genome Research Institute
Affiliation as printed
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA
National Human Genome Research Institute
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Affiliation as printed
Genetic Epidemiology Group, Department of Population Health Sciences, University of Leicester, Leicester, UK
University of Leicester
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University of Michigan · Institute for Social Research
Affiliation as printed
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
University of Groningen, University Medical Center Groningen
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Washington University in St. Louis
Affiliation as printed
Cardiovascular Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, St. Louis, MO, USA
Washington University in St. Louis
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Affiliation as printed
Lothian Birth Cohorts, Psychology, The University of Edinburgh, Edinburgh, UK
The University of Edinburgh
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Vanderbilt University · Vanderbilt University Medical Center
Affiliation as printed
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Vanderbilt University Medical Center
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Affiliation as printed
Division of General Neurology, Department of Neurology, Medical University of Graz, Graz, Austria
Division of Neuroradiology, Interventional and Vascular Radiology, Department of Radiology, Medical University of Graz, Graz, Austria
Medical University of Graz
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Brigham and Women's Hospital · Harvard University
Affiliation as printed
Division of Sleep and Circadian Disorders, Department of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA
Division of Sleep and Circadian Disorders, Department of Medicine, Harvard Medical School, Boston, MA, USA
Brigham and Women's Hospital
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University of Michigan · Institute for Social Research
Affiliation as printed
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
University of Michigan
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Affiliation as printed
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
University of Eastern Finland
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Inserm · Université de Lille · Institut Pasteur de Lille · Approches épidémiologiques et moléculaires intégratives visant à améliorer la compréhension des maladies chroniques liées au vieillissement
Affiliation as printed
Lille University; Lille University Hospital; INSERM U1167 - RID-AGE; Institut Pasteur de Lille, University of Lille, Inserm, Institut Pasteur de Lille, Lille, France
University of Lille, Inserm, Institut Pasteur de Lille
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University of Wisconsin–Madison
Affiliation as printed
Cardiovascular Medicine, Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
University of Wisconsin School of Medicine and Public Health
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Affiliation as printed
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
University of Regensburg
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Universitätsmedizin Greifswald · German Center for Neurodegenerative Diseases · Universität Greifswald
Affiliation as printed
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
German Centre for Neurodegenerative Diseases, Site Rostock/Greifswald, Greifswald, Germany
University Medicine Greifswald
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University of North Carolina at Chapel Hill
Affiliation as printed
Gillings School of Global Public Health, Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
The University of North Carolina at Chapel Hill
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Washington University in St. Louis
Affiliation as printed
Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, St. Louis, MO, USA
Washington University in St. Louis
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The University of Texas Southwestern Medical Center
Affiliation as printed
Department of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
University of Texas Southwestern Medical Center
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Affiliation as printed
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland
University of Eastern Finland, Kuopio Campus
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University of Alabama at Birmingham
Affiliation as printed
Epidemiology, UAB School of Public Health, Birmingham, Alabama, USA
UAB School of Public Health
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