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.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders / M. 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, J. Yang, A. Lundby, J.H. Zhao, Y.J. Kim, M.J. Go, P. Almgren, M. Bochud, G. Boucher, M.C. Cornelis, D. 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. 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. 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, K.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. 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 FB, H.V. Huikuri, D.J. Hunter, C. Iribarren, B. Isomaa, M.R. Jarvelin, 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. Willer, L. Franke. - In: NATURE GENETICS. - ISSN 1061-4036. - 45:6(2013 Jun), pp. 621-631.

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

C. Barlassina;D. Cusi;
2013

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.
Settore MED/14 - Nefrologia
giu-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/221909
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