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Genetic insights into resting heart rate and its role in cardiovascular disease

Author

Listed:
  • Yordi J. Vegte

    (University Medical Center Groningen)

  • Ruben N. Eppinga

    (Isala Zwolle ziekenhuis)

  • M. Yldau Ende

    (University medical Center Utrecht)

  • Yanick P. Hagemeijer

    (University Medical Center Groningen
    University of Groningen)

  • Yuvaraj Mahendran

    (University of Copenhagen)

  • Elias Salfati

    (Stanford University School of Medicine
    University of Iceland)

  • Albert V. Smith

    (University of Michigan)

  • Vanessa Y. Tan

    (University of Bristol
    University of Bristol)

  • Dan E. Arking

    (Johns Hopkins University School of Medicine)

  • Ioanna Ntalla

    (Queen Mary University of London)

  • Emil V. Appel

    (University of Copenhagen)

  • Claudia Schurmann

    (The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai)

  • Jennifer A. Brody

    (Medicine, University of Washington)

  • Rico Rueedi

    (University of Lausanne
    Swiss Institute of Bioinformatics)

  • Ozren Polasek

    (University of Split School of Medicine
    Algebra LAB, Algebra University College)

  • Gardar Sveinbjornsson

    (deCODE genetics / Amgen Inc.)

  • Cecile Lecoeur

    (UMR 8199, University of Lille Nord de France)

  • Claes Ladenvall

    (Uppsala University
    Lund University)

  • Jing Hua Zhao

    (University of Cambridge)

  • Aaron Isaacs

    (Maastricht University)

  • Lihua Wang

    (Washington University School of Medicine)

  • Jian’an Luan

    (MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine)

  • Shih-Jen Hwang

    (Division of Intramural Research, National Heart Lung and Blood Institute, NIH, USA)

  • Nina Mononen

    (Fimlab Laboratories
    Tampere University)

  • Kirsi Auro

    (, National Institute for Health and Welfare, Finland
    University of Helsinki)

  • Anne U. Jackson

    (University of Michigan)

  • Lawrence F. Bielak

    (University of Michigan)

  • Linyao Zeng

    (Technische Universität München)

  • Nabi Shah

    (University of Dundee
    COMSATS University Islamabad)

  • Maria Nethander

    (Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
    Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg)

  • Archie Campbell

    (Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh
    Usher Institute for Population Health Sciences and Informatics, The University of Edinburgh)

  • Tuomo Rankinen

    (Human Genomics Laboratory, Pennington Biomedical Research Center)

  • Sonali Pechlivanis

    (Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen)

  • Lu Qi

    (Department of Epidemiology, Tulane University)

  • Wei Zhao

    (University of Michigan
    Survey Research Center, Institute for Social Research, University of Michigan)

  • Federica Rizzi

    (Unit of Biomedicine, Bio4Dreams-Business Nursery for Life Sciences)

  • Toshiko Tanaka

    (Longitudinal Study Section, National Institute on Aging)

  • Antonietta Robino

    (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”)

  • Massimiliano Cocca

    (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”)

  • Leslie Lange

    (Medicine, University of Colorado Anschutz Medical Campus)

  • Martina Müller-Nurasyid

    (IBE, Ludwig-Maximilians-University Munich, LMU Munich
    Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University
    Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health)

  • Carolina Roselli

    (Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Weihua Zhang

    (Imperial College London
    London North West University Healthcare NHS Trust)

  • Marcus E. Kleber

    (University of Heidelberg
    SYNLAB MVZ Humangenetik Mannheim)

  • Xiuqing Guo

    (Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
    Harbor-UCLA Medical Center)

  • Henry J. Lin

    (Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
    Harbor-UCLA Medical Center)

  • Francesca Pavani

    (Institute for Biomedicine, Eurac Research)

  • Tessel E. Galesloot

    (Radboud university medical center)

  • Raymond Noordam

    (Leiden University Medical Center)

  • Yuri Milaneschi

    (Amsterdam UMC, Vrije Universiteit, Amsterdam)

  • Katharina E. Schraut

    (Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh)

  • Marcel Hoed

    (Uppsala University and Science for Life Laboratory)

  • Frauke Degenhardt

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel)

  • Stella Trompet

    (Leiden University Medical Center
    Department of Cardiology, Leiden University Medical Center)

  • Marten E. Berg

    (Erasmus Medical Center)

  • Giorgio Pistis

    (Institute of Genetics and Biomedic Research (IRGB), Italian National Research Council (CNR)
    Center for Statistical Genetics, University of Michigan)

  • Yih-Chung Tham

    (Singapore Eye Research Institute, Singapore National Eye Centre)

  • Stefan Weiss

    (Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), Partner Site Greifswald)

  • Xueling S. Sim

    (Saw Swee Hock School of Public Health, National University Health System and National University of Singapore)

  • Hengtong L. Li

    (Singapore Eye Research Institute, Singapore National Eye Centre)

  • Peter J. Most

    (University of Groningen, University Medical Center Groningen)

  • Ilja M. Nolte

    (University of Groningen, University Medical Center Groningen)

  • Leo-Pekka Lyytikäinen

    (Fimlab Laboratories
    Tampere University
    Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge)

  • M. Abdullah Said

    (University Medical Center Groningen)

  • Daniel R. Witte

    (Aarhus University)

  • Carlos Iribarren

    (Division of Research, Kaiser Permenente of Northern California
    The Scripps Research Institute)

  • Lenore Launer

    (National Institute on Aging)

  • Susan M. Ring

    (University of Bristol
    University of Bristol)

  • Paul S. Vries

    (University of Texas Health Science Center at Houston, School of Public Health)

  • Peter Sever

    (National Heart and Lung Institute, Imperial College London)

  • Allan Linneberg

    (Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital
    University of Copenhagen)

  • Erwin P. Bottinger

    (The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
    The Icahn School of Medicine at Mount Sinai)

  • Sandosh Padmanabhan

    (Institute of Cardiovascular and Medical Sciences, University of Glasgow)

  • Bruce M. Psaty

    (University of Washington)

  • Nona Sotoodehnia

    (University of Washington)

  • Ivana Kolcic

    (University of Split School of Medicine
    Algebra LAB, Algebra University College)

  • David O. Arnar

    (deCODE genetics / Amgen Inc.
    Faculty of Medicine, School of Health Sciences, University of Iceland
    Landspitali—The National University Hospital of Iceland)

  • Daniel F. Gudbjartsson

    (deCODE genetics / Amgen Inc.
    School of Engineering and Natural Sciences, University of Iceland)

  • Hilma Holm

    (deCODE genetics / Amgen Inc.)

  • Beverley Balkau

    (Centre for Research in Epidemiology and Population Health, Institut national de la santé et de la recherche médicale
    UMRS 1018, University Versailles Saint-Quentin-en-Yvelines
    UMRS 1018, University Paris Sud)

  • Claudia T. Silva

    (Genetic Epidemiology Unit, Dept. of Epidemiology, Erasmus University Medical Center)

  • Christopher H. Newton-Cheh

    (Cardiology Section, Massachusetts general hospital,)

  • Kjell Nikus

    (Tampere University Hospital
    Tampere University)

  • Perttu Salo

    (, National Institute for Health and Welfare, Finland
    University of Helsinki)

  • Karen L. Mohlke

    (University of North Carolina)

  • Patricia A. Peyser

    (University of Michigan)

  • Heribert Schunkert

    (Technische Universität München
    Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance)

  • Mattias Lorentzon

    (Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
    Region Västra Götaland, Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
    Mary McKillop Institute for Health Research, Australian Catholic University)

  • Jari Lahti

    (University of Helsinki)

  • Dabeeru C. Rao

    (Division of Biostatistics, Washington University)

  • Marilyn C. Cornelis

    (Preventive Medicine, Northwestern University)

  • Jessica D. Faul

    (Survey Research Center, Institute for Social Research, University of Michigan)

  • Jennifer A. Smith

    (University of Michigan
    Survey Research Center, Institute for Social Research, University of Michigan)

  • Katarzyna Stolarz-Skrzypek

    (Jagiellonian University Medical College)

  • Stefania Bandinelli

    (Geriatric Unit, Unità sanitaria locale Toscana Centro)

  • Maria Pina Concas

    (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”)

  • Gianfranco Sinagra

    (Cardiovascular Department, “Ospedali Riuniti and University of Trieste”)

  • Thomas Meitinger

    (Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München
    Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health)

  • Melanie Waldenberger

    (Research Unit Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
    Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
    German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance)

  • Moritz F. Sinner

    (German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance
    University Hospital, LMU Munich)

  • Konstantin Strauch

    (Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University
    Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
    Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich)

  • Graciela E. Delgado

    (University of Heidelberg)

  • Kent D. Taylor

    (Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
    Harbor-UCLA Medical Center)

  • Jie Yao

    (Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
    Harbor-UCLA Medical Center)

  • Luisa Foco

    (Institute for Biomedicine, Eurac Research)

  • Olle Melander

    (Lund University and Skåne University Hospital
    Lund University)

  • Jacqueline Graaf

    (Radboud university medical center)

  • Renée Mutsert

    (Leiden University Medical Center)

  • Eco J. C. Geus

    (Biological Psychology, EMGO+ Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University)

  • Åsa Johansson

    (Uppsala University)

  • Peter K. Joshi

    (University of Edinburgh)

  • Lars Lind

    (Uppsala University Hospital)

  • Andre Franke

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel)

  • Peter W. Macfarlane

    (University of Glasgow)

  • Kirill V. Tarasov

    (Laboratory of Cardiovascular Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health)

  • Nicholas Tan

    (Singapore Eye Research Institute, Singapore National Eye Centre)

  • Stephan B. Felix

    (DZHK (German Center for Cardiovascular Research), Partner Site Greifswald
    University Medicine Greifswald)

  • E-Shyong Tai

    (Singapore Eye Research Institute, Singapore National Eye Centre
    National University of Singapore)

  • Debra Q. Quek

    (Singapore Eye Research Institute, Singapore National Eye Centre)

  • Harold Snieder

    (University of Groningen, University Medical Center Groningen)

  • Johan Ormel

    (University Medical Center Groningen)

  • Martin Ingelsson

    (Uppsala University)

  • Cecilia Lindgren

    (Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Andrew P. Morris

    (Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Olli T. Raitakari

    (Centre for Population Health Research, University of Turku and Turku University Hospital
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
    Turku University Hospital)

  • Torben Hansen

    (University of Copenhagen)

  • Themistocles Assimes

    (Stanford University School of Medicine)

  • Vilmundur Gudnason

    (University of Iceland
    Icelandic Heart Association)

  • Nicholas J. Timpson

    (MRC Integrative Epidemiology Unit, University of Bristol
    Population Health Sciences, Bristol Medical School,, University of Bristol)

  • Alanna C. Morrison

    (University of Texas Health Science Center at Houston, School of Public Health)

  • Patricia B. Munroe

    (Queen Mary University of London
    NIHR Barts Biomedical Research Centre, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London)

  • David P. Strachan

    (Population Health Research Institute, St George’s, University of London)

  • Niels Grarup

    (University of Copenhagen)

  • Ruth J. F. Loos

    (University of Copenhagen
    The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
    The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai)

  • Susan R. Heckbert

    (University of Washington)

  • Peter Vollenweider

    (Lausanne University hospital)

  • Caroline Hayward

    (MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh)

  • Kari Stefansson

    (deCODE genetics / Amgen Inc.
    Faculty of Medicine, School of Health Sciences, University of Iceland)

  • Philippe Froguel

    (Imperial College London
    Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, Lille University Hospital, EGID
    University of Lille)

  • Leif Groop

    (Lund University
    University of Helsinki)

  • Nicholas J. Wareham

    (MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine)

  • Cornelia M. Duijn

    (Genetic Epidemiology Unit, Dept. of Epidemiology, Erasmus University Medical Center)

  • Mary F. Feitosa

    (Washington University School of Medicine)

  • Christopher J. O’Donnell

    (Cardiology Section, VA Boston Healthcare System, Harvard Medical School)

  • Mika Kähönen

    (Tampere University Hospital
    Tampere University)

  • Markus Perola

    (, National Institute for Health and Welfare, Finland
    University of Helsinki)

  • Michael Boehnke

    (University of Michigan)

  • Sharon L. R. Kardia

    (University of Michigan)

  • Jeanette Erdmann

    (University of Lübeck)

  • Colin N. A. Palmer

    (University of Dundee)

  • Claes Ohlsson

    (Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
    Sahlgrenska University Hospital)

  • David J. Porteous

    (University of Edinburgh)

  • Johan G. Eriksson

    (University of Helsinki
    National University of Singapore
    Public health Research Program, Folkhalsan Research Center)

  • Claude Bouchard

    (Human Genomics Laboratory, Pennington Biomedical Research Center)

  • Susanne Moebus

    (Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen
    Centre for Urban Epidemiology, University Hospital of Essen, University Duisburg-Essen)

  • Peter Kraft

    (Epidemiology, Harvard T.H. Chan School of Public Health)

  • David R. Weir

    (Survey Research Center, Institute for Social Research, University of Michigan)

  • Daniele Cusi

    (Unit of Biomedicine, Bio4Dreams-Business Nursery for Life Sciences
    Institute of Biomedical Technologies, National Research Council of Italy)

  • Luigi Ferrucci

    (Longitudinal Study Section, National Institute on Aging)

  • Sheila Ulivi

    (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”)

  • Giorgia Girotto

    (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”
    University of Trieste)

  • Adolfo Correa

    (Jackson Heart Study, University of Mississippi Medical Center)

  • Stefan Kääb

    (German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance
    University Hospital, LMU Munich)

  • Annette Peters

    (Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
    German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance
    Chair of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München)

  • John C. Chambers

    (Imperial College London
    London North West University Healthcare NHS Trust
    Lee Kong Chian School of Medicine, Nanyang Technological University)

  • Jaspal S. Kooner

    (London North West University Healthcare NHS Trust
    National Heart and Lung Institute, Imperial College London
    Imperial College Healthcare NHS Trust, Imperial College London)

  • Winfried März

    (University of Heidelberg
    Synlab Academy, Synlab Holding Deutschland GmbH)

  • Jerome I. Rotter

    (Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
    Harbor-UCLA Medical Center)

  • Andrew A. Hicks

    (Institute for Biomedicine, Eurac Research)

  • J. Gustav Smith

    (Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital
    Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University
    The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital)

  • Lambertus A. L. M. Kiemeney

    (Radboud university medical center)

  • Dennis O. Mook-Kanamori

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Brenda W. J. H. Penninx

    (Amsterdam UMC, Vrije Universiteit, Amsterdam)

  • Ulf Gyllensten

    (Uppsala University)

  • James F. Wilson

    (University of Edinburgh
    MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh)

  • Stephen Burgess

    (MRC Biostatistics Unit, University of Cambridge)

  • Johan Sundström

    (Uppsala University Hospital)

  • Wolfgang Lieb

    (Institute of Epidemiology and Biobank PopGen, Kiel University)

  • J. Wouter Jukema

    (Department of Cardiology, Leiden University Medical Center
    Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center
    Netherlands Heart Institute)

  • Mark Eijgelsheim

    (Erasmus Medical Center
    University Medical Center Groningen)

  • Edward L. M. Lakatta

    (Laboratory of Cardiovascular Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health)

  • Ching-Yu Cheng

    (Singapore Eye Research Institute, Singapore National Eye Centre
    Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School
    National University of Singapore)

  • Marcus Dörr

    (DZHK (German Center for Cardiovascular Research), Partner Site Greifswald
    University Medicine Greifswald)

  • Tien-Yin Wong

    (Singapore Eye Research Institute, Singapore National Eye Centre
    Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School
    Tsinghua Medicine, Tsinghua University)

  • Charumathi Sabanayagam

    (Singapore Eye Research Institute, Singapore National Eye Centre
    Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School)

  • Albertine J. Oldehinkel

    (University of Groningen, University Medical Center Groningen)

  • Harriette Riese

    (University Medical Center Groningen)

  • Terho Lehtimäki

    (Fimlab Laboratories
    Tampere University)

  • Niek Verweij

    (University Medical Center Groningen)

  • Pim Harst

    (University Medical Center Groningen
    University medical Center Utrecht
    University Medical Center Groningen)

Abstract

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Suggested Citation

  • Yordi J. Vegte & Ruben N. Eppinga & M. Yldau Ende & Yanick P. Hagemeijer & Yuvaraj Mahendran & Elias Salfati & Albert V. Smith & Vanessa Y. Tan & Dan E. Arking & Ioanna Ntalla & Emil V. Appel & Claudi, 2023. "Genetic insights into resting heart rate and its role in cardiovascular disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39521-2
    DOI: 10.1038/s41467-023-39521-2
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    References listed on IDEAS

    as
    1. Niek Verweij & Yordi J. van de Vegte & Pim van der Harst, 2018. "Genetic study links components of the autonomous nervous system to heart-rate profile during exercise," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    2. Tanya M. Teslovich & Kiran Musunuru & Albert V. Smith & Andrew C. Edmondson & Ioannis M. Stylianou & Masahiro Koseki & James P. Pirruccello & Samuli Ripatti & Daniel I. Chasman & Cristen J. Willer & C, 2010. "Biological, clinical and population relevance of 95 loci for blood lipids," Nature, Nature, vol. 466(7307), pages 707-713, August.
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