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 Bochud; Gabrielle 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; Themistocles L. Assimes; 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; Jacques S. Beckmann; 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

doi:10.1038/ng.2610

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, Themistocles L. Assimes, 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, Jacques S. Beckmann, 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^*

^*Corresponding author for this work

261 Citations (Scopus)

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 language	English
Journal	Nature Genetics
Volume	45
Issue number	6
Pages (from-to)	621-631
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2610
Publication status	Published - 06.2013

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality

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Research Area: Medical Genetics

Access to Document

10.1038/ng.2610

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

@article{41e62dee6d1442e180bfa120767a0290,

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.",

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

year = "2013",

month = jun,

doi = "10.1038/ng.2610",

language = "English",

volume = "45",

pages = "621--631",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Den Hoed, M, Eijgelsheim, M, Esko, T, Brundel, BJJM, Peal, DS, Evans, DM, Nolte, IM, Segrè, AV, Holm, H, Handsaker, RE, Westra, HJ, Johnson, T, Isaacs, A, Yang, J, Lundby, A, Zhao, JH, Kim, YJ, Go, MJ, Almgren, P, Bochud, M, Boucher, G, Cornalis, MC, Gudbjartsson, D, Hadley, D, Van Der Harst, P, Hayward, C, Den Heijer, M, Igl, W, Jackson, AU, Kutalik, Z, Luan, JA, 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, PIW, 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, Å, 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, MRP, Marques-Vidal, P, Leach, IM, 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, JCM, Wong, A, Wong, Q, Jamshidi, Y, Zitting, P, Boer, JMA, Boomsma, DI, Borecki, IB, Van Duijn, CM, Ekelund, U, Forouhi, NG, Froguel, P, Hingorani, A, Ingelsson, E, Kivimaki, M, Kronmal, RA, Kuh, D, Lind, L, Martin, NG, Oostra, BA, Pedersen, NL, Assimes, TL, Rotter, JI, Van Der Schouw, YT, Verschuren, WMM, Walker, M, Albanes, D, Arnar, DO, Assimes, TL, Bandinelli, S, Boehnke, M, De Boer, RA, Bouchard, C, W L Mark Caulfield, LMC, 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, Jarvelin, MR, Jula, A, Kähönen, M, Kiemeney, LA, Van Der Klauw, MM, Kooner, JS, Kraft, P, Iacoviello, L, Lehtimäki, T, Lokki, MLL, 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, Beckmann, JS, 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, C, 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, RJF 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

TY - JOUR

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

AU - Den Hoed, Marcel

AU - Eijgelsheim, Mark

AU - Esko, Tõnu

AU - Brundel, Bianca J.J.M.

AU - Peal, David S.

AU - Evans, David M.

AU - Nolte, Ilja M.

AU - Segrè, Ayellet V.

AU - Holm, Hilma

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PY - 2013/6

Y1 - 2013/6

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.

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.

UR - https://www.scopus.com/pages/publications/84878726099

U2 - 10.1038/ng.2610

DO - 10.1038/ng.2610

M3 - Journal articles

C2 - 23583979

AN - SCOPUS:84878726099

SN - 1061-4036

VL - 45

SP - 621

EP - 631

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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