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

M.A.H. den Hoed, M. Eijgelsheim, T. Esko, B.J. Brundel, D.S. Peal, D.M. Evans, I.M. Nolte, A.V. Segrè, H. Holm, R.E. Handsaker, H.J. Westra, T. Johnson, A. Isaacs, L. Yang, A. Lundby, J.H. Zhao, Y.J. Kim, M.J. Go, P. Almgren, M. BochudG. Boucher, M.C. Cornelis, D.F. Gudbjartsson, D. Hadley, P. van der Harst, C. Hayward, M. den Heijer, W. Igl, A.U. Jackson, Z. Kutalik, J. Luan, J.P. Kemp, K. Kristiansson, C. Ladenvall, M. Lorentzon, M.E. Montasser, O.T. Njajou, P.F. O'Reilly, S. Padmanabhan, B. St Pourcain, T. Rankinen, P. Salo, T. Tanaka, N.J. Timpson, V. Vitart, L. Waite, W. Wheeler, W. Zhang, H.H.M. Draisma, M.F. Feitosa, K.F. Kerr, P.A. Lind, E. Mihailov, N.C. Onland-Moret, C. Song, M.N. Weedon, W. Xie, L. Yengo, D. Absher, C.M. Albert, A. Alonso, D.E. Arking, P.I. de Bakker, B. Balkau, C. Barlassina, P. Benaglio, J.C. Bis, N. Bouatia-Naji, S. Brage, S.J. Chanock, P.S. Chines, M. Chung, D. Darbar, C. Dina, M. Dörr, P. Elliott, S.B. Felix, K. Fischer, C. Fuchsberger, E.J.C. de Geus, P. Goyette, V. Gudnason, T.B. Harris, A.L. Hartikainen, A.S. Havulinna, S.R. Heckbert, A.A. Hicks, A. Hofman, S. Holewijn, F. Hoogstra-Berends, J.J. Hottenga, M.K. Jensen, A. Johansson, J. Junttila, S. Kääb, B. Kanon, S. Ketkar, K.T. Khaw, J.W. Knowles, A.S. Kooner, J.A. Kors, M. Kumari, L. Milani, P. Laiho, E.G. Lakatta, C. Langenberg, M. Leusink, Y. Liu, R.N. Luben, K.L. Lunetta, S.N. Lynch, M.R. Markus, P. Marques-Vidal, I. Mateo Leach, W.L. McArdle, S.A. McCarroll, S.E. Medland, K.A. Miller, G.W. Montgomery, A.C. Morrison, M. Müller-Nurasyid, P. Navarro, M. Nelis, J.R. O'Connell, C.J. O'Donnell, K.K. Ong, A.B. Newman, A. Peters, O. Polasek, A. Pouta, P.P. Pramstaller, B.M. Psaty, D.C. Rao, S.M. Ring, E.J. Rossin, D. Rudan, S. Sanna, R.A. Scott, J.S. Sehmi, S. Sharp, J.T. Shin, A.B. Singleton, A.V. Smith, N. Soranzo, T.D. Spector, C. Stewart, H.M. Stringham, K.V. Tarasov, A.G. Uitterlinden, L. Vandenput, S.J. Hwang, J.B. Whitfield, C. Wijmenga, S.H. Wild, G. Willemsen, J.F. Wilson, J.C. Witteman, A. Wong, Q. Wong, Y. Jamshidi, P. Zitting, J.M. Boer, D.I. Boomsma, I.B. Borecki, C.M. van Duijn, U. Ekelund, N.G. Forouhi, P. Froguel, A.D. Hingorani, E. Ingelsson, M. Kivimaki, R.A. Kronmal, D Kuh, L. Lind, N.G. Martin, B.A. Oostra, N.L. Pedersen, T. Quertermous, J.I. Rotter, Y.T. van der Schouw, W.M. Verschuren, M. Walker, D. Albanes, D.O. Arnar, T.L. Assimes, S. Bandinelli, M. Boehnke, R.A. de Boer, C. Bouchard, W.L. Caulfield, J.C. Chambers, G. Curhan, D. Cusi, J. Eriksson, L. Ferrucci, W.H. van Gilst, N. Glorioso, J. de Graaf, L. Groop, U. Gyllensten, W.C. Hsueh, F.B. Hu, H.V. Huikuri, D.J. Hunter, C. Iribarren, B. Isomaa, M.R. Järvelin, A. Jula, M. Kähönen, L.A. Kiemeney, M.M. van der Klauw, J.S. Kooner, P. Kraft, L. Iacoviello, T. Lehtimäki, M.L. Lokki, B.D. Mitchell, G. Navis, M.S. Nieminen, C. Ohlsson, N.R. Poulter, L. Qi, O.T. Raitakari, E.B. Rimm, J.D. Rioux, F. Rizzi, I. Rudan, V. Salomaa, P.S. Sever, D.C. Shields, A.R. Shuldiner, J. Sinisalo, A.V. Stanton, R.P. Stolk, D.P. Strachan, J.C. Tardif, U. Thorsteinsdottir, J. Tuomilehto, D.J. van Veldhuisen, J. Virtamo, J. Viikari, P. Vollenweider, G. Waeber, E. Widen, Y.S. Cho, J.V. Olsen, P.M. Visscher, C.J. Willer, L Franke, J. Erdmann, J.R. Thompson, A. Pfeufer, N. Sotoodehnia, C. Newton-Cheh, P.T. Ellinor, B.H.C. Stricker, A. Metspalu, M. Perola, J.S. Beckmann, G.D. Smith, K. Stefansson, N.J. Wareham, P.B. Munroe, O.C.M. Sibon, D.J. Milan, H. Snieder, N.J. Samani, R.J. Loos

Research output: Contribution to JournalArticleAcademicpeer-review

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. © 2013 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)621-631
JournalNature Genetics
Volume45
Issue number6
DOIs
Publication statusPublished - 2013

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