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. Bochud; G. 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

doi:10.1038/ng.2610

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

Biological Psychology

Research output: Contribution to Journal › Article › Academic › peer-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 language	English
Pages (from-to)	621-631
Journal	Nature Genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2610
Publication status	Published - 2013

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10.1038/ng.2610

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den Hoed, M. A. H., Eijgelsheim, M., Esko, T., Brundel, B. J., 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, L., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., ... Loos, R. J. (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

den Hoed, M.A.H. ; Eijgelsheim, M. ; Esko, T. ; Brundel, B.J. ; 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, L. ; Lundby, A. ; Zhao, J.H. ; Kim, Y.J. ; Go, M.J. ; Almgren, P. ; Bochud, M. ; Boucher, G. ; Cornelis, M.C. ; Gudbjartsson, D.F. ; Hadley, D. ; van der Harst, P. ; Hayward, C. ; den Heijer, M. ; Igl, W. ; Jackson, A.U. ; Kutalik, Z. ; Luan, J. ; Kemp, J.P. ; Kristiansson, K. ; Ladenvall, C. ; Lorentzon, M. ; Montasser, M.E. ; Njajou, O.T. ; O'Reilly, P.F. ; Padmanabhan, S. ; St Pourcain, B. ; Rankinen, T. ; Salo, P. ; Tanaka, T. ; Timpson, N.J. ; Vitart, V. ; Waite, L. ; Wheeler, W. ; Zhang, W. ; Draisma, H.H.M. ; Feitosa, M.F. ; Kerr, K.F. ; Lind, P.A. ; Mihailov, E. ; Onland-Moret, N.C. ; Song, C. ; Weedon, M.N. ; Xie, W. ; Yengo, L. ; Absher, D. ; Albert, C.M. ; Alonso, A. ; Arking, D.E. ; de Bakker, P.I. ; Balkau, B. ; Barlassina, C. ; Benaglio, P. ; Bis, J.C. ; Bouatia-Naji, N. ; Brage, S. ; Chanock, S.J. ; Chines, P.S. ; Chung, M. ; Darbar, D. ; Dina, C. ; Dörr, M. ; Elliott, P. ; Felix, S.B. ; Fischer, K. ; Fuchsberger, C. ; de Geus, E.J.C. ; Goyette, P. ; Gudnason, V. ; Harris, T.B. ; Hartikainen, A.L. ; Havulinna, A.S. ; Heckbert, S.R. ; Hicks, A.A. ; Hofman, A. ; Holewijn, S. ; Hoogstra-Berends, F. ; Hottenga, J.J. ; Jensen, M.K. ; Johansson, A. ; Junttila, J. ; Kääb, S. ; Kanon, B. ; Ketkar, S. ; Khaw, K.T. ; Knowles, J.W. ; Kooner, A.S. ; Kors, J.A. ; Kumari, M. ; Milani, L. ; Laiho, P. ; Lakatta, E.G. ; Langenberg, C. ; Leusink, M. ; Liu, Y. ; Luben, R.N. ; Lunetta, K.L. ; Lynch, S.N. ; Markus, M.R. ; Marques-Vidal, P. ; Mateo Leach, I. ; McArdle, W.L. ; McCarroll, S.A. ; Medland, S.E. ; Miller, K.A. ; Montgomery, G.W. ; Morrison, A.C. ; Müller-Nurasyid, M. ; Navarro, P. ; Nelis, M. ; O'Connell, J.R. ; O'Donnell, C.J. ; Ong, K.K. ; Newman, A.B. ; Peters, A. ; Polasek, O. ; Pouta, A. ; Pramstaller, P.P. ; Psaty, B.M. ; Rao, D.C. ; Ring, S.M. ; Rossin, E.J. ; Rudan, D. ; Sanna, S. ; Scott, R.A. ; Sehmi, J.S. ; Sharp, S. ; Shin, J.T. ; Singleton, A.B. ; Smith, A.V. ; Soranzo, N. ; Spector, T.D. ; Stewart, C. ; Stringham, H.M. ; Tarasov, K.V. ; Uitterlinden, A.G. ; Vandenput, L. ; Hwang, S.J. ; Whitfield, J.B. ; Wijmenga, C. ; Wild, S.H. ; Willemsen, G. ; Wilson, J.F. ; Witteman, J.C. ; Wong, A. ; Wong, Q. ; Jamshidi, Y. ; Zitting, P. ; Boer, J.M. ; Boomsma, D.I. ; Borecki, I.B. ; van Duijn, C.M. ; Ekelund, U. ; Forouhi, N.G. ; Froguel, P. ; Hingorani, A.D. ; Ingelsson, E. ; Kivimaki, M. ; Kronmal, R.A. ; Kuh, D ; Lind, L. ; Martin, N.G. ; Oostra, B.A. ; Pedersen, N.L. ; Quertermous, T. ; Rotter, J.I. ; van der Schouw, Y.T. ; Verschuren, W.M. ; Walker, M. ; Albanes, D. ; Arnar, D.O. ; Assimes, T.L. ; Bandinelli, S. ; Boehnke, M. ; de Boer, R.A. ; Bouchard, C. ; Caulfield, W.L. ; Chambers, J.C. ; Curhan, G. ; Cusi, D. ; Eriksson, J. ; Ferrucci, L. ; van Gilst, W.H. ; Glorioso, N. ; de Graaf, J. ; Groop, L. ; Gyllensten, U. ; Hsueh, W.C. ; Hu, F.B. ; Huikuri, H.V. ; Hunter, D.J. ; Iribarren, C. ; Isomaa, B. ; Järvelin, M.R. ; Jula, A. ; Kähönen, M. ; Kiemeney, L.A. ; van der Klauw, M.M. ; Kooner, J.S. ; Kraft, P. ; Iacoviello, L. ; Lehtimäki, T. ; Lokki, M.L. ; Mitchell, B.D. ; Navis, G. ; Nieminen, M.S. ; Ohlsson, C. ; Poulter, N.R. ; Qi, L. ; Raitakari, O.T. ; Rimm, E.B. ; Rioux, J.D. ; Rizzi, F. ; Rudan, I. ; Salomaa, V. ; Sever, P.S. ; Shields, D.C. ; Shuldiner, A.R. ; Sinisalo, J. ; Stanton, A.V. ; Stolk, R.P. ; Strachan, D.P. ; Tardif, J.C. ; Thorsteinsdottir, U. ; Tuomilehto, J. ; van Veldhuisen, D.J. ; Virtamo, J. ; Viikari, J. ; Vollenweider, P. ; Waeber, G. ; Widen, E. ; Cho, Y.S. ; Olsen, J.V. ; Visscher, P.M. ; Willer, C.J. ; Franke, L ; Erdmann, J. ; Thompson, J.R. ; Pfeufer, A. ; Sotoodehnia, N. ; Newton-Cheh, C. ; Ellinor, P.T. ; Stricker, B.H.C. ; Metspalu, A. ; Perola, M. ; Beckmann, J.S. ; Smith, G.D. ; Stefansson, K. ; Wareham, N.J. ; Munroe, P.B. ; Sibon, O.C.M. ; Milan, D.J. ; Snieder, H. ; Samani, N.J. ; Loos, R.J. / Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. In: Nature Genetics. 2013 ; Vol. 45, No. 6. pp. 621-631.

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title = "Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders",

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. {\textcopyright} 2013 Nature America, Inc. All rights reserved.",

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

year = "2013",

doi = "10.1038/ng.2610",

language = "English",

volume = "45",

pages = "621--631",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

den Hoed, MAH, Eijgelsheim, M, Esko, T, Brundel, BJ, Peal, DS, Evans, DM, Nolte, IM, Segrè, AV, Holm, H, Handsaker, RE, Westra, HJ, Johnson, T, Isaacs, A, Yang, L, Lundby, A, Zhao, JH, Kim, YJ, Go, MJ, Almgren, P, Bochud, M, Boucher, G, Cornelis, MC, Gudbjartsson, DF, Hadley, D, van der Harst, P, Hayward, C, den Heijer, M, Igl, W, Jackson, AU, Kutalik, Z, Luan, J, Kemp, JP, Kristiansson, K, Ladenvall, C, Lorentzon, M, Montasser, ME, Njajou, OT, O'Reilly, PF, Padmanabhan, S, St Pourcain, B, Rankinen, T, Salo, P, Tanaka, T, Timpson, NJ, Vitart, V, Waite, L, Wheeler, W, Zhang, W, Draisma, HHM, Feitosa, MF, Kerr, KF, Lind, PA, Mihailov, E, Onland-Moret, NC, Song, C, Weedon, MN, Xie, W, Yengo, L, Absher, D, Albert, CM, Alonso, A, Arking, DE, de Bakker, PI, Balkau, B, Barlassina, C, Benaglio, P, Bis, JC, Bouatia-Naji, N, Brage, S, Chanock, SJ, Chines, PS, Chung, M, Darbar, D, Dina, C, Dörr, M, Elliott, P, Felix, SB, Fischer, K, Fuchsberger, C, de Geus, EJC, Goyette, P, Gudnason, V, Harris, TB, Hartikainen, AL, Havulinna, AS, Heckbert, SR, Hicks, AA, Hofman, A, Holewijn, S, Hoogstra-Berends, F, Hottenga, JJ, Jensen, MK, Johansson, A, Junttila, J, Kääb, S, Kanon, B, Ketkar, S, Khaw, KT, Knowles, JW, Kooner, AS, Kors, JA, Kumari, M, Milani, L, Laiho, P, Lakatta, EG, Langenberg, C, Leusink, M, Liu, Y, Luben, RN, Lunetta, KL, Lynch, SN, Markus, MR, Marques-Vidal, P, Mateo Leach, I, McArdle, WL, McCarroll, SA, Medland, SE, Miller, KA, Montgomery, GW, Morrison, AC, Müller-Nurasyid, M, Navarro, P, Nelis, M, O'Connell, JR, O'Donnell, CJ, Ong, KK, Newman, AB, Peters, A, Polasek, O, Pouta, A, Pramstaller, PP, Psaty, BM, Rao, DC, Ring, SM, Rossin, EJ, Rudan, D, Sanna, S, Scott, RA, Sehmi, JS, Sharp, S, Shin, JT, Singleton, AB, Smith, AV, Soranzo, N, Spector, TD, Stewart, C, Stringham, HM, Tarasov, KV, Uitterlinden, AG, Vandenput, L, Hwang, SJ, Whitfield, JB, Wijmenga, C, Wild, SH, Willemsen, G, Wilson, JF, Witteman, JC, Wong, A, Wong, Q, Jamshidi, Y, Zitting, P, Boer, JM, Boomsma, DI, Borecki, IB, van Duijn, CM, Ekelund, U, Forouhi, NG, Froguel, P, Hingorani, AD, Ingelsson, E, Kivimaki, M, Kronmal, RA, Kuh, D, Lind, L, Martin, NG, Oostra, BA, Pedersen, NL, Quertermous, T, Rotter, JI, van der Schouw, YT, Verschuren, WM, Walker, M, Albanes, D, Arnar, DO, Assimes, TL, Bandinelli, S, Boehnke, M, de Boer, RA, Bouchard, C, Caulfield, WL, Chambers, JC, Curhan, G, Cusi, D, Eriksson, J, Ferrucci, L, van Gilst, WH, Glorioso, N, de Graaf, J, Groop, L, Gyllensten, U, Hsueh, WC, Hu, FB, Huikuri, HV, Hunter, DJ, Iribarren, C, Isomaa, B, Järvelin, MR, Jula, A, Kähönen, M, Kiemeney, LA, van der Klauw, MM, Kooner, JS, Kraft, P, Iacoviello, L, Lehtimäki, T, Lokki, ML, Mitchell, BD, Navis, G, Nieminen, MS, Ohlsson, C, Poulter, NR, Qi, L, Raitakari, OT, Rimm, EB, Rioux, JD, Rizzi, F, Rudan, I, Salomaa, V, Sever, PS, Shields, DC, Shuldiner, AR, Sinisalo, J, Stanton, AV, Stolk, RP, Strachan, DP, Tardif, JC, Thorsteinsdottir, U, Tuomilehto, J, van Veldhuisen, DJ, Virtamo, J, Viikari, J, Vollenweider, P, Waeber, G, Widen, E, Cho, YS, Olsen, JV, Visscher, PM, Willer, CJ, Franke, L, Erdmann, J, Thompson, JR, Pfeufer, A, Sotoodehnia, N, Newton-Cheh, C, Ellinor, PT, Stricker, BHC, Metspalu, A, Perola, M, Beckmann, JS, Smith, GD, Stefansson, K, Wareham, NJ, Munroe, PB, Sibon, OCM, Milan, DJ, Snieder, H, Samani, NJ & Loos, RJ 2013, 'Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders', Nature Genetics, vol. 45, no. 6, pp. 621-631. https://doi.org/10.1038/ng.2610

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

In: Nature Genetics, Vol. 45, No. 6, 2013, p. 621-631.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

AU - den Hoed, M.A.H.

AU - Eijgelsheim, M.

AU - Esko, T.

AU - Brundel, B.J.

AU - Peal, D.S.

AU - Evans, D.M.

AU - Nolte, I.M.

AU - Segrè, A.V.

AU - Holm, H.

AU - Handsaker, R.E.

AU - Westra, H.J.

AU - Johnson, T.

AU - Isaacs, A.

AU - Yang, L.

AU - Lundby, A.

AU - Zhao, J.H.

AU - Kim, Y.J.

AU - Go, M.J.

AU - Almgren, P.

AU - Bochud, M.

AU - Boucher, G.

AU - Cornelis, M.C.

AU - Gudbjartsson, D.F.

AU - Hadley, D.

AU - van der Harst, P.

AU - Hayward, C.

AU - den Heijer, M.

AU - Igl, W.

AU - Jackson, A.U.

AU - Kutalik, Z.

AU - Luan, J.

AU - Kemp, J.P.

AU - Kristiansson, K.

AU - Ladenvall, C.

AU - Lorentzon, M.

AU - Montasser, M.E.

AU - Njajou, O.T.

AU - O'Reilly, P.F.

AU - Padmanabhan, S.

AU - St Pourcain, B.

AU - Rankinen, T.

AU - Salo, P.

AU - Tanaka, T.

AU - Timpson, N.J.

AU - Vitart, V.

AU - Waite, L.

AU - Wheeler, W.

AU - Zhang, W.

AU - Draisma, H.H.M.

AU - Feitosa, M.F.

AU - Kerr, K.F.

AU - Lind, P.A.

AU - Mihailov, E.

AU - Onland-Moret, N.C.

AU - Song, C.

AU - Weedon, M.N.

AU - Xie, W.

AU - Yengo, L.

AU - Absher, D.

AU - Albert, C.M.

AU - Alonso, A.

AU - Arking, D.E.

AU - de Bakker, P.I.

AU - Balkau, B.

AU - Barlassina, C.

AU - Benaglio, P.

AU - Bis, J.C.

AU - Bouatia-Naji, N.

AU - Brage, S.

AU - Chanock, S.J.

AU - Chines, P.S.

AU - Chung, M.

AU - Darbar, D.

AU - Dina, C.

AU - Dörr, M.

AU - Elliott, P.

AU - Felix, S.B.

AU - Fischer, K.

AU - Fuchsberger, C.

AU - de Geus, E.J.C.

AU - Goyette, P.

AU - Gudnason, V.

AU - Harris, T.B.

AU - Hartikainen, A.L.

AU - Havulinna, A.S.

AU - Heckbert, S.R.

AU - Hicks, A.A.

AU - Hofman, A.

AU - Holewijn, S.

AU - Hoogstra-Berends, F.

AU - Hottenga, J.J.

AU - Jensen, M.K.

AU - Johansson, A.

AU - Junttila, J.

AU - Kääb, S.

AU - Kanon, B.

AU - Ketkar, S.

AU - Khaw, K.T.

AU - Knowles, J.W.

AU - Kooner, A.S.

AU - Kors, J.A.

AU - Kumari, M.

AU - Milani, L.

AU - Laiho, P.

AU - Lakatta, E.G.

AU - Langenberg, C.

AU - Leusink, M.

AU - Liu, Y.

AU - Luben, R.N.

AU - Lunetta, K.L.

AU - Lynch, S.N.

AU - Markus, M.R.

AU - Marques-Vidal, P.

AU - Mateo Leach, I.

AU - McArdle, W.L.

AU - McCarroll, S.A.

AU - Medland, S.E.

AU - Miller, K.A.

AU - Montgomery, G.W.

AU - Morrison, A.C.

AU - Müller-Nurasyid, M.

AU - Navarro, P.

AU - Nelis, M.

AU - O'Connell, J.R.

AU - O'Donnell, C.J.

AU - Ong, K.K.

AU - Newman, A.B.

AU - Peters, A.

AU - Polasek, O.

AU - Pouta, A.

AU - Pramstaller, P.P.

AU - Psaty, B.M.

AU - Rao, D.C.

AU - Ring, S.M.

AU - Rossin, E.J.

AU - Rudan, D.

AU - Sanna, S.

AU - Scott, R.A.

AU - Sehmi, J.S.

AU - Sharp, S.

AU - Shin, J.T.

AU - Singleton, A.B.

AU - Smith, A.V.

AU - Soranzo, N.

AU - Spector, T.D.

AU - Stewart, C.

AU - Stringham, H.M.

AU - Tarasov, K.V.

AU - Uitterlinden, A.G.

AU - Vandenput, L.

AU - Hwang, S.J.

AU - Whitfield, J.B.

AU - Wijmenga, C.

AU - Wild, S.H.

AU - Willemsen, G.

AU - Wilson, J.F.

AU - Witteman, J.C.

AU - Wong, A.

AU - Wong, Q.

AU - Jamshidi, Y.

AU - Zitting, P.

AU - Boer, J.M.

AU - Boomsma, D.I.

AU - Borecki, I.B.

AU - van Duijn, C.M.

AU - Ekelund, U.

AU - Forouhi, N.G.

AU - Froguel, P.

AU - Hingorani, A.D.

AU - Ingelsson, E.

AU - Kivimaki, M.

AU - Kronmal, R.A.

AU - Kuh, D

AU - Lind, L.

AU - Martin, N.G.

AU - Oostra, B.A.

AU - Pedersen, N.L.

AU - Quertermous, T.

AU - Rotter, J.I.

AU - van der Schouw, Y.T.

AU - Verschuren, W.M.

AU - Walker, M.

AU - Albanes, D.

AU - Arnar, D.O.

AU - Assimes, T.L.

AU - Bandinelli, S.

AU - Boehnke, M.

AU - de Boer, R.A.

AU - Bouchard, C.

AU - Caulfield, W.L.

AU - Chambers, J.C.

AU - Curhan, G.

AU - Cusi, D.

AU - Eriksson, J.

AU - Ferrucci, L.

AU - van Gilst, W.H.

AU - Glorioso, N.

AU - de Graaf, J.

AU - Groop, L.

AU - Gyllensten, U.

AU - Hsueh, W.C.

AU - Hu, F.B.

AU - Huikuri, H.V.

AU - Hunter, D.J.

AU - Iribarren, C.

AU - Isomaa, B.

AU - Järvelin, M.R.

AU - Jula, A.

AU - Kähönen, M.

AU - Kiemeney, L.A.

AU - van der Klauw, M.M.

AU - Kooner, J.S.

AU - Kraft, P.

AU - Iacoviello, L.

AU - Lehtimäki, T.

AU - Lokki, M.L.

AU - Mitchell, B.D.

AU - Navis, G.

AU - Nieminen, M.S.

AU - Ohlsson, C.

AU - Poulter, N.R.

AU - Qi, L.

AU - Raitakari, O.T.

AU - Rimm, E.B.

AU - Rioux, J.D.

AU - Rizzi, F.

AU - Rudan, I.

AU - Salomaa, V.

AU - Sever, P.S.

AU - Shields, D.C.

AU - Shuldiner, A.R.

AU - Sinisalo, J.

AU - Stanton, A.V.

AU - Stolk, R.P.

AU - Strachan, D.P.

AU - Tardif, J.C.

AU - Thorsteinsdottir, U.

AU - Tuomilehto, J.

AU - van Veldhuisen, D.J.

AU - Virtamo, J.

AU - Viikari, J.

AU - Vollenweider, P.

AU - Waeber, G.

AU - Widen, E.

AU - Cho, Y.S.

AU - Olsen, J.V.

AU - Visscher, P.M.

AU - Willer, C.J.

AU - Franke, L

AU - Erdmann, J.

AU - Thompson, J.R.

AU - Pfeufer, A.

AU - Sotoodehnia, N.

AU - Newton-Cheh, C.

AU - Ellinor, P.T.

AU - Stricker, B.H.C.

AU - Metspalu, A.

AU - Perola, M.

AU - Beckmann, J.S.

AU - Smith, G.D.

AU - Stefansson, K.

AU - Wareham, N.J.

AU - Munroe, P.B.

AU - Sibon, O.C.M.

AU - Milan, D.J.

AU - Snieder, H.

AU - Samani, N.J.

AU - Loos, R.J.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1038/ng.2610

DO - 10.1038/ng.2610

M3 - Article

VL - 45

SP - 621

EP - 631

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -

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

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