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

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, Claudia Schurmann, Jennifer A. Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian’an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U. Jackson, Lawrence F. Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E. Kleber, Xiuqing Guo, Henry J. Lin, Francesca Pavani, Tessel E. Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E. Schraut, Marcel Hoed, Frauke Degenhardt, Stella Trompet, Marten E. Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S. Sim, Hengtong L. Li, Peter J. Most, Ilja M. Nolte, Leo-Pekka Lyytikäinen, M. Abdullah Said, Daniel R. Witte, Carlos Iribarren, Lenore Launer, Susan M. Ring, Paul S. Vries, Peter Sever, Allan Linneberg, Erwin P. Bottinger, Sandosh Padmanabhan, Bruce M. Psaty, Nona Sotoodehnia, Ivana Kolcic, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T. Silva, Christopher H. Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L. Mohlke, Patricia A. Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C. Rao, Marilyn C. Cornelis, Jessica D. Faul, Jennifer A. Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F. Sinner, Konstantin Strauch, Graciela E. Delgado, Kent D. Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline Graaf, Renée Mutsert, Eco J. C. Geus, Åsa Johansson, Peter K. Joshi, Lars Lind, Andre Franke, Peter W. Macfarlane, Kirill V. Tarasov, Nicholas Tan, Stephan B. Felix, E-Shyong Tai, Debra Q. Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P. Morris, Olli T. Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J. Timpson, Alanna C. Morrison, Patricia B. Munroe, David P. Strachan, Niels Grarup, Ruth J. F. Loos, Susan R. Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J. Wareham, Cornelia M. Duijn, Mary F. Feitosa, Christopher J. O’Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes Ohlsson, David J. Porteous, Johan G. Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R. Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C. Chambers, Jaspal S. Kooner, Winfried März, Jerome I. Rotter, Andrew A. Hicks, J. Gustav Smith, Lambertus A. L. M. Kiemeney, Dennis O. Mook-Kanamori, Brenda W. J. H. Penninx, Ulf Gyllensten, James F. Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J. Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij and Pim Harst ()
Additional contact information
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
Yuvaraj Mahendran: University of Copenhagen
Elias Salfati: Stanford University School of Medicine
Albert V. Smith: University of Michigan
Vanessa Y. Tan: 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
Ozren Polasek: University of Split School of Medicine
Gardar Sveinbjornsson: deCODE genetics / Amgen Inc.
Cecile Lecoeur: UMR 8199, University of Lille Nord de France
Claes Ladenvall: Uppsala 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
Kirsi Auro: , National Institute for Health and Welfare, Finland
Anne U. Jackson: University of Michigan
Lawrence F. Bielak: University of Michigan
Linyao Zeng: Technische Universität München
Nabi Shah: University of Dundee
Maria Nethander: Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
Archie Campbell: Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, 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
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
Carolina Roselli: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
Weihua Zhang: Imperial College London
Marcus E. Kleber: University of Heidelberg
Xiuqing Guo: Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
Henry J. Lin: Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
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
Marten E. Berg: Erasmus Medical Center
Giorgio Pistis: Institute of Genetics and Biomedic Research (IRGB), Italian National Research Council (CNR)
Yih-Chung Tham: Singapore Eye Research Institute, Singapore National Eye Centre
Stefan Weiss: Interfaculty Institute for Genetics and Functional Genomics, University Medicine 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
M. Abdullah Said: University Medical Center Groningen
Daniel R. Witte: Aarhus University
Carlos Iribarren: Division of Research, Kaiser Permenente of Northern California
Lenore Launer: National Institute on Aging
Susan M. Ring: 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
Erwin P. Bottinger: The Charles Bronfman Institute for Personalized Medicine, 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
David O. Arnar: deCODE genetics / Amgen Inc.
Daniel F. Gudbjartsson: deCODE genetics / Amgen Inc.
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
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
Perttu Salo: , National Institute for Health and Welfare, Finland
Karen L. Mohlke: University of North Carolina
Patricia A. Peyser: University of Michigan
Heribert Schunkert: Technische Universität München
Mattias Lorentzon: Sahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
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
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
Melanie Waldenberger: Research Unit Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
Moritz F. Sinner: German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance
Konstantin Strauch: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University
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
Jie Yao: Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
Luisa Foco: Institute for Biomedicine, Eurac Research
Olle Melander: Lund University and Skåne University Hospital
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
E-Shyong Tai: Singapore Eye Research Institute, Singapore National Eye Centre
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
Torben Hansen: University of Copenhagen
Themistocles Assimes: Stanford University School of Medicine
Vilmundur Gudnason: University of Iceland
Nicholas J. Timpson: MRC Integrative Epidemiology Unit, 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
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
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.
Philippe Froguel: Imperial College London
Leif Groop: Lund University
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
Markus Perola: , National Institute for Health and Welfare, Finland
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
David J. Porteous: University of Edinburgh
Johan G. Eriksson: University of Helsinki
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
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
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”
Adolfo Correa: Jackson Heart Study, University of Mississippi Medical Center
Stefan Kääb: German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance
Annette Peters: Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health
John C. Chambers: Imperial College London
Jaspal S. Kooner: London North West University Healthcare NHS Trust
Winfried März: University of Heidelberg
Jerome I. Rotter: Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA
Andrew A. Hicks: Institute for Biomedicine, Eurac Research
J. Gustav Smith: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital
Lambertus A. L. M. Kiemeney: Radboud university medical center
Dennis O. Mook-Kanamori: Leiden University Medical Center
Brenda W. J. H. Penninx: Amsterdam UMC, Vrije Universiteit, Amsterdam
Ulf Gyllensten: Uppsala University
James F. Wilson: 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
Mark Eijgelsheim: Erasmus Medical Center
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
Marcus Dörr: DZHK (German Center for Cardiovascular Research), Partner Site Greifswald
Tien-Yin Wong: Singapore Eye Research Institute, Singapore National Eye Centre
Charumathi Sabanayagam: Singapore Eye Research Institute, Singapore National Eye Centre
Albertine J. Oldehinkel: University of Groningen, University Medical Center Groningen
Harriette Riese: University Medical Center Groningen
Terho Lehtimäki: Fimlab Laboratories
Niek Verweij: University Medical Center Groningen
Pim Harst: University Medical Center Groningen

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39521-2

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