Genetic insights into resting heart rate and its role in cardiovascular disease
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 ,   The DCCT/EDIC Research Group, 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 , van der Harst Pim 
Published: August 2023

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.