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Cited by 298

The DOI matches its Crossref record; 15 of the 15 references it cites were found in a registry or an index.

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

Open access
Global BPgen Consortium, den Hoed, Marcel, CARDIoGRAM Consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, CHARGE-AF Consortium, Eijgelsheim, Mark, Esko, Tõnu, Brundel, Bianca J J M, Peal, David S, Evans, David M, Nolte, Ilja M, Segrè, Ayellet V, Holm, Hilma, Handsaker, Robert E, Westra, Harm-Jan, Johnson, Toby, Isaacs, Aaron, Yang, Jian, Lundby, Alicia, Zhao, Jing Hua, Kim, Young Jin, Go, Min Jin, Almgren, Peter, Bochud, Murielle, Boucher, Gabrielle, Cornelis, Marilyn C, Gudbjartsson, Daniel, Hadley, David, van der Harst, Pim, Hayward, Caroline, den Heijer, Martin, Igl, Wilmar, Jackson, Anne U, Kutalik, Zoltán, Luan, Jian'an, Kemp, John P, Kristiansson, Kati, Ladenvall, Claes, Lorentzon, Mattias, Montasser, May E, Njajou, Omer T, O'Reilly, Paul F, Padmanabhan, Sandosh, St. Pourcain, Beate, Rankinen, Tuomo, Salo, Perttu, Tanaka, Toshiko, Timpson, Nicholas J, Vitart, Veronique, Waite, Lindsay, Wheeler, William, Zhang, Weihua, Draisma, Harmen H M, Feitosa, Mary F, Kerr, Kathleen F, Lind, Penelope A, Mihailov, Evelin, Onland-Moret, N Charlotte, Song, Ci, Weedon, Michael N, Xie, Weijia, Yengo, Loic, Absher, Devin, Albert, Christine M, Alonso, Alvaro, Arking, Dan E, de Bakker, Paul I W, Balkau, Beverley, Barlassina, Cristina, Benaglio, Paola, Bis, Joshua C, Bouatia-Naji, Nabila, Brage, Søren, Chanock, Stephen J, Chines, Peter S, Chung, Mina, Darbar, Dawood, Dina, Christian, Dörr, Marcus, Elliott, Paul, Felix, Stephan B, Fischer, Krista, Fuchsberger, Christian, de Geus, Eco J C, Goyette, Philippe, Gudnason, Vilmundur, Harris, Tamara B, Hartikainen, Anna-Liisa, Havulinna, Aki S, Heckbert, Susan R, Hicks, Andrew A, Hofman, Albert, Holewijn, Suzanne, Hoogstra-Berends, Femke, Hottenga, Jouke-Jan, Jensen, Majken K, Johansson, Åsa, Junttila, Juhani, Kääb, Stefan, Kanon, Bart, Ketkar, Shamika, Khaw, Kay-Tee, Knowles, Joshua W, Kooner, Angrad S, Kors, Jan A, Kumari, Meena, Milani, Lili, Laiho, Päivi, Lakatta, Edward G, Langenberg, Claudia, Leusink, Maarten, Liu, Yongmei, Luben, Robert N, Lunetta, Kathryn L, Lynch, Stacey N, Markus, Marcello R P, Marques-Vidal, Pedro, Leach, Irene Mateo, McArdle, Wendy L, McCarroll, Steven A, Medland, Sarah E, Miller, Kathryn A, Montgomery, Grant W, Morrison, Alanna C, Müller-Nurasyid, Martina, Navarro, Pau, Nelis, Mari, O'Connell, Jeffrey R, O'Donnell, Christopher J, Ong, Ken K, Newman, Anne B, Peters, Annette, Polasek, Ozren, Pouta, Anneli, Pramstaller, Peter P, Psaty, Bruce M, Rao, Dabeeru C, Ring, Susan M, Rossin, Elizabeth J, Rudan, Diana, Sanna, Serena, Scott, Robert A, Sehmi, Jaban S, Sharp, Stephen, Shin, Jordan T, Singleton, Andrew B, Smith, Albert V, Soranzo, Nicole, Spector, Tim D, Stewart, Chip, Stringham, Heather M, Tarasov, Kirill V, Uitterlinden, André G, Vandenput, Liesbeth, Hwang, Shih-Jen, Whitfield, John B, Wijmenga, Cisca, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Witteman, Jacqueline C M, Wong, Andrew, Wong, Quenna, Jamshidi, Yalda, Zitting, Paavo, Boer, Jolanda M A, Boomsma, Dorret I, Borecki, Ingrid B, van Duijn, Cornelia M, Ekelund, Ulf, Forouhi, Nita G, Froguel, Philippe, Hingorani, Aroon, Ingelsson, Erik, Kivimaki, Mika, Kronmal, Richard A, Kuh, Diana, Lind, Lars, Martin, Nicholas G, Oostra, Ben A, Pedersen, Nancy L, Quertermous, Thomas, Rotter, Jerome I, van der Schouw, Yvonne T, Verschuren, W M Monique, Walker, Mark, Albanes, Demetrius, Arnar, David O, Assimes, Themistocles L, Bandinelli, Stefania, Boehnke, Michael, de Boer, Rudolf A, Bouchard, Claude, Caulfield, W L Mark, Chambers, John C, Curhan, Gary, Cusi, Daniele, Eriksson, Johan, Ferrucci, Luigi, van Gilst, Wiek H, Glorioso, Nicola, de Graaf, Jacqueline, Groop, Leif, Gyllensten, Ulf, Hsueh, Wen-Chi, Hu, Frank B, Huikuri, Heikki V, Hunter, David J, Iribarren, Carlos, Isomaa, Bo, Jarvelin, Marjo-Riitta, Jula, Antti, Kähönen, Mika, Kiemeney, Lambertus A, van der Klauw, Melanie M, Kooner, Jaspal S, Kraft, Peter, Iacoviello, Licia, Lehtimäki, Terho, Lokki, Marja-Liisa L, Mitchell, Braxton D, Navis, Gerjan, Nieminen, Markku S, Ohlsson, Claes, Poulter, Neil R, Qi, Lu, Raitakari, Olli T, Rimm, Eric B, Rioux, John D, Rizzi, Federica, Rudan, Igor, Salomaa, Veikko, Sever, Peter S, Shields, Denis C, Shuldiner, Alan R, Sinisalo, Juha, Stanton, Alice V, Stolk, Ronald P, Strachan, David P, Tardif, Jean-Claude, Thorsteinsdottir, Unnur, Tuomilehto, Jaako, van Veldhuisen, Dirk J, Virtamo, Jarmo, Viikari, Jorma, Vollenweider, Peter, Waeber, Gérard, Widen, Elisabeth, Cho, Yoon Shin, Olsen, Jesper V, Visscher, Peter M, Willer, Cristen, Franke, Lude, Erdmann, Jeanette, Thompson, John R, Pfeufer, Arne, Sotoodehnia, Nona, Newton-Cheh, Christopher, Ellinor, Patrick T, Stricker, Bruno H Ch, Metspalu, Andres, Perola, Markus, Beckmann, Jacques S, Smith, George Davey, Stefansson, Kari, Wareham, Nicholas J, Munroe, Patricia B, Sibon, Ody C M, Milan, David J, Snieder, Harold, Samani, Nilesh J, Loos, Ruth J F·2013·Nature Genetics
DOI 10.1038/ng.2610
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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.

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  1. Dyer, A.R. et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am. J. Epidemiol. 112, 736–749 (1980). · DOI · Paper page
  2. Gillum, R.F., Makuc, D.M. & Feldman, J.J. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study. Am. Heart J. 121, 172–177 (1991). · DOI · Paper page
  3. Nauman, J., Janszky, I., Vatten, L.J. & Wisloff, U. Temporal changes in resting heart rate and deaths from ischemic heart disease. J. Am. Med. Assoc. 306, 2579–2587 (2011). · DOI · Paper page
  4. Schwartz, P.J., Billman, G.E. & Stone, H.L. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation 69, 790–800 (1984). · DOI · Paper page
  5. Beere, P.A., Glagov, S. & Zarins, C.K. Retarding effect of lowered heart rate on coronary atherosclerosis. Science 226, 180–182 (1984). · DOI · Paper page
  6. Beere, P.A., Glagov, S. & Zarins, C.K. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey. Localization, compensatory enlargement, and the sparing effect of lowered heart rate. Arterioscler. Thromb. 12, 1245–1253 (1992). · DOI
  7. Böhm, M. et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 376, 886–894 (2010). · DOI · Paper page
  8. Dalageorgou, C. et al. Heritability of QT interval: how much is explained by genes for resting heart rate? J. Cardiovasc. Electrophysiol. 19, 386–391 (2008). · DOI
  9. De Geus, E.J., Kupper, N., Boomsma, D.I. & Snieder, H. Bivariate genetic modeling of cardiovascular stress reactivity: does stress uncover genetic variance? Psychosom. Med. 69, 356–364 (2007). · DOI
  10. Russell, M.W., Law, I., Sholinsky, P. & Fabsitz, R.R. Heritability of ECG measurements in adult male twins. J. Electrocardiol. 30 (suppl.), 64–68 (1998). · DOI
  11. Cho, Y.S. et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41, 527–534 (2009). · DOI · Paper page
  12. Eijgelsheim, M. et al. Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum. Mol. Genet. 19, 3885–3894 (2010). · DOI
  13. Holm, H. et al. Several common variants modulate heart rate, PR interval and QRS duration. Nat. Genet. 42, 117–122 (2010). · DOI · Paper page
  14. Inoue, T. et al. Higher heart rate predicts the risk of developing hypertension in a normotensive screened cohort. Circ. J. 71, 1755–1760 (2007). · DOI
  15. Pfeufer, A. et al. Genome-wide association study of PR interval. Nat. Genet. 42, 153–159 (2010). · DOI · Paper page
  16. Sotoodehnia, N. et al. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat. Genet. 42, 1068–1076 (2010). · DOI
  17. Holm, H. et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 43, 316–320 (2011). · DOI
  18. Levy, R.L. et al. Transient tachycardia; prognostic significance alone and in association with transient hypertension. Med. Press Egypt 38, 207–212 (1946).
  19. Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009). · DOI · Paper page
  20. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011). · DOI · Paper page
  21. Kusumoto, F.M. & Goldschlager, N. Cardiac pacing. N. Engl. J. Med. 334, 89–97 (1996). · DOI
  22. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009). · DOI · Paper page
  23. Guan, Y. & Stephens, M. Practical issues in imputation-based association mapping. PLoS Genet. 4, e1000279 (2008). · DOI
  24. Ellinghaus, D., Schreiber, S., Franke, A. & Nothnagel, M. Current software for genotype imputation. Hum. Genomics 3, 371–380 (2009). · DOI
  25. Pei, Y.F., Zhang, L., Li, J. & Deng, H.W. Analyses and comparison of imputation-based association methods. PLoS ONE 5, e10827 (2010). · DOI
  26. Abecasis, G.R. & Wigginton, J.E. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am. J. Hum. Genet. 77, 754–767 (2005). · DOI · Paper page
  27. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010). · DOI · Paper page
  28. Voight, B.F. et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 8, e1002793 (2012). · DOI · Paper page
  29. Newton-Cheh, C. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399–406 (2009). · DOI · Paper page
  30. Thomas, P.D. et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 13, 2129–2141 (2003). · DOI
  31. Lundby, A. et al. Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat. Commun. 3, 876 (2012). · DOI · Paper page
  32. Dubois, P.C. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42, 295–302 (2010). · DOI · Paper page
  33. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008). · DOI · Paper page
  34. Handsaker, R.E., Korn, J.M., Nemesh, J. & McCarroll, S.A. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. Nat. Genet. 43, 269–276 (2011). · DOI · Paper page
  35. Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007). · DOI · Paper page
  36. Zhang, D. et al. Effects of different small HSPB members on contractile dysfunction and structural changes in a Drosophila melanogaster model for atrial fibrillation. J. Mol. Cell Cardiol. 51, 381–389 (2011). · DOI
  37. Burns, C.G. et al. High-throughput assay for small molecules that modulate zebrafish embryonic heart rate. Nat. Chem. Biol. 1, 263–264 (2005). · DOI
  38. Shin, J.T., Pomerantsev, E.V., Mably, J.D. & MacRae, C.A. High-resolution cardiovascular function confirms functional orthology of myocardial contractility pathways in zebrafish. Physiol. Genomics 42, 300–309 (2010). · DOI

Cited by

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Metadata

Authors
Global BPgen Consortium, den Hoed, M., CARDIoGRAM Consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, CHARGE-AF Consortium, 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., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., 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. W., 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, Å., 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. P., Marques-Vidal, P., Leach, I. M., 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. M., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M. A., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., 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. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L. M., 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., Jarvelin, 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. 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., 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. F.
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2013-04-14
Volume
45
Issue
6
Pages
621-631
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.2610
OpenAlex
W1992911777
Cited by
298
References
15
FWCI
17.58
Type
journal article
Language
en
Open access
bronze
Licence
www.springer.com/tdm (tdm)

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Global BPgen Consortium, den Hoed, M., CARDIoGRAM Consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, CHARGE-AF Consortium, 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., . . . Loos, R. J. F. (2013). Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders. Nature Genetics. https://doi.org/10.1038/ng.2610

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