Genetic insights into resting heart rate and its role in cardiovascular disease
Journal article
van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, ... van der Harst, Pim. (2023). Genetic insights into resting heart rate and its role in cardiovascular disease. Nature Communications. 14(1), p. Article 4646. https://doi.org/10.1038/s41467-023-39521-2
Authors | van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian’an, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Guo, Xiuqing, Lin, Henry J., Pavani, Francesca, Galesloot, Tessel E., Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina E., den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten E., Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling S., Li, Hengtong L., van der Most, Peter J., Nolte, Ilja M., Lyytikäinen, Leo-Pekka, Said, M. Abdullah, Witte, Daniel R., Iribarren, Carlos, Launer, Lenore, Ring, Susan M., de Vries, Paul S., Sever, Peter, Linneberg, Allan, Bottinger, Erwin P., Padmanabhan, Sandosh, Psaty, Bruce M., Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz, Paterson, Andrew D., Arnar, David O., Gudbjartsson, Daniel F., Holm, Hilma, Balkau, Beverley, Silva, Claudia T., Newton-Cheh, Christopher H., Nikus, Kjell, Salo, Perttu, Mohlke, Karen L., Peyser, Patricia A., Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru C., Cornelis, Marilyn C., Faul, Jessica D., Smith, Jennifer A., Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, Sinner, Moritz F., Strauch, Konstantin, Delgado, Graciela E., Taylor, Kent D., Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renée, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre, Macfarlane, Peter W., Tarasov, Kirill V., Tan, Nicholas, Felix, Stephan B., Tai, E. Shyong, Quek, Debra Q., Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia, Morris, Andrew P., Raitakari, Olli T., Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur, Timpson, Nicholas J., Morrison, Alanna C., Munroe, Patricia B., Strachan, David P., Grarup, Niels, Loos, Ruth J. F., Heckbert, Susan R., Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif, Wareham, Nicholas J., van Duijn, Cornelia M., Feitosa, Mary F., O’Donnell, Christopher J., Kähönen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes, Porteous, David J., Eriksson, Johan G., Bouchard, Claude, Moebus, Susanne, Kraft, Peter, Weir, David R., Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kääb, Stefan, Peters, Annette, Chambers, John C., Kooner, Jaspal S., März, Winfried, Rotter, Jerome I., Hicks, Andrew A., Smith, J. Gustav, Kiemeney, Lambertus A. L. M., Mook-Kanamori, Dennis O., Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James F., Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Dörr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi, Oldehinkel, Albertine J., Riese, Harriette, Lehtimäki, Terho, Verweij, Niek and van der Harst, Pim |
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Abstract | Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development. |
Year | 2023 |
Journal | Nature Communications |
Journal citation | 14 (1), p. Article 4646 |
Publisher | Nature Publishing Group |
ISSN | 2041-1723 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s41467-023-39521-2 |
PubMed ID | 37532724 |
Scopus EID | 2-s2.0-85166440619 |
PubMed Central ID | PMC10397318 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-21 |
Funder | NWO Veni |
GlaxoSmithKline | |
Wellcome Trust | |
University of Bristol | |
Biomedical Research Centre (BRC), National Institute for Health Research | |
Medical Research Council (MRC), United Kingdom | |
Cancer Research UK (CRUK) | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 02 Aug 2023 |
Publication process dates | |
Accepted | 16 Jun 2023 |
Deposited | 07 May 2025 |
Grant ID | 016.186.125 |
202802/Z/16/Z | |
217065/Z/19/Z | |
BRC-1215-2001 | |
MC_UU_00011/1 | |
C18281/A29019 | |
Additional information | A detailed list of acknowledgements and funding is provided in Supplementary Data 1 (https://www.nature.com/articles/s41467-023-39521-2#MOESM4) per cohort. |
© The Author(s) 2023, corrected publication 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
https://acuresearchbank.acu.edu.au/item/91vq2/genetic-insights-into-resting-heart-rate-and-its-role-in-cardiovascular-disease
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OA_van_de_Vegte_2023_Genetic_insights_into_resting_heart_rate.pdf | |
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