Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Marcel Den Hoed, Mark Eijgelsheim, Tõnu Esko, Bianca J.J.M. Brundel, David S. Peal, David M. Evans, Ilja M. Nolte, Ayellet V. Segrè, Hilma Holm, Robert E. Handsaker, Harm Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle BochudGabrielle Boucher, Marilyn C. Cornalis, Daniel Gudbjartsson, David Hadley, Pim Van Der Harst, Caroline Hayward, Martin Den Heijer, Wilmar Igl, Anne U. Jackson, Zoltán Kutalik, Jian'An Luan, John P. Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E. Montasser, Omer T. Njajou, Paul F. O'Reilly, Sandosh Padmanabhan, Beate St. Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J. Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H.M. Draisma, Mary F. Feitosa, Kathleen F. Kerr, Penelope A. Lind, Evelin Mihailov, N. Charlotte Onland-Moret, Ci Song, Michael N. Weedon, Weijia Xie, Loic Yengo, Devin Absher, Christine M. Albert, Alvaro Alonso, Dan E. Arking, Paul I.W. De Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C. Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J. Chanock, Peter S. Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B. Felix, Krista Fischer, Christian Fuchsberger, Eco J.C. De Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B. Harris, Anna Liisa Hartikainen, Aki S. Havulinna, Susan R. Heckbert, Andrew A. Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke Jan Hottenga, Majken K. Jensen, Åsa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay Tee Khaw, Joshua W. Knowles, Angrad S. Kooner, Jan A. Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G. Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N. Luben, Kathryn L. Lunetta, Stacey N. Lynch, Marcello R.P. Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L. McArdle, Steven A. McCarroll, Sarah E. Medland, Kathryn A. Miller, Grant W. Montgomery, Alanna C. Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R. O'Connell, Christopher J. O'Donnell, Ken K. Ong, Anne B. Newman, Annette Peters, Ozren Polasek, Anneli Pouta, Peter P. Pramstaller, Bruce M. Psaty, Dabeeru C. Rao, Susan M. Ring, Elizabeth J. Rossin, Diana Rudan, Serena Sanna, Robert A. Scott, Jaban S. Sehmi, Stephen Sharp, Jordan T. Shin, Andrew B. Singleton, Albert V. Smith, Nicole Soranzo, Tim D. Spector, Chip Stewart, Heather M. Stringham, Kirill V. Tarasov, André G. Uitterlinden, Liesbeth Vandenput, Shih Jen Hwang, John B. Whitfield, Cisca Wijmenga, Sarah H. Wild, Gonneke Willemsen, James F. Wilson, Jacqueline C.M. Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M.A. Boer, Dorret I. Boomsma, Ingrid B. Borecki, Cornelia M. Van Duijn, Ulf Ekelund, Nita G. Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimaki, Richard A. Kronmal, Diana Kuh, Lars Lind, Nicholas G. Martin, Ben A. Oostra, Nancy L. Pedersen, Thomas Quertermous, Jerome I. Rotter, Yvonne T. Van Der Schouw, W. M.Monique Verschuren, Mark Walker, Demetrius Albanes, David O. Arnar, Themistocles L. Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A. De Boer, Claude Bouchard, L Mark Caulfield W L Mark Caulfield, John C. Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H. Van Gilst, Nicola Glorioso, Jacqueline De Graaf, Leif Groop, Ulf Gyllensten, Wen Chi Hsueh, Frank B. Hu, Heikki V. Huikuri, David J. Hunter, Carlos Iribarren, Bo Isomaa, Marjo Riitta Jarvelin, Antti Jula, Mika Kähönen, Lambertus A. Kiemeney, Melanie M. Van Der Klauw, Jaspal S. Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja Liisa L. Lokki, Braxton D. Mitchell, Gerjan Navis, Markku S. Nieminen, Claes Ohlsson, Neil R. Poulter, Lu Qi, Olli T. Raitakari, Eric B. Rimm, John D. Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S. Sever, Denis C. Shields, Alan R. Shuldiner, Juha Sinisalo, Alice V. Stanton, Ronald P. Stolk, David P. Strachan, Jean Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J. Van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widen, Yoon Shin Cho, Jesper V. Olsen, Peter M. Visscher, Cristen Willer, Lude Franke, Jeanette Erdmann, John R. Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T. Ellinor, Bruno H.Ch Stricker, Andres Metspalu, Markus Perola, Jacques S. Beckmann, George Davey Smith, Kari Stefansson, Nicholas J. Wareham, Patricia B. Munroe, Ody C.M. Sibon, David J. Milan, Harold Snieder, Nilesh J. Samani, Ruth J.F. Loos

Research output: Contribution to journalArticle

Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Original languageEnglish (US)
Pages (from-to)621-631
Number of pages11
JournalNature genetics
Volume45
Issue number6
DOIs
StatePublished - Jun 1 2013

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ASJC Scopus subject areas

  • Genetics

Cite this

Den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J. J. M., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H. J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., ... Loos, R. J. F. (2013). Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics, 45(6), 621-631. https://doi.org/10.1038/ng.2610