TY - JOUR
T1 - Genetic insights into resting heart rate and its role in cardiovascular disease
AU - The DCCT/EDIC Research Group
AU - van de Vegte, Yordi J.
AU - Eppinga, Ruben N.
AU - van der Ende, M. Yldau
AU - Hagemeijer, Yanick P.
AU - Mahendran, Yuvaraj
AU - Salfati, Elias
AU - Smith, Albert V.
AU - Tan, Vanessa Y.
AU - Arking, Dan E.
AU - Ntalla, Ioanna
AU - Appel, Emil V.
AU - Schurmann, Claudia
AU - Brody, Jennifer A.
AU - Rueedi, Rico
AU - Polasek, Ozren
AU - Sveinbjornsson, Gardar
AU - Lecoeur, Cecile
AU - Ladenvall, Claes
AU - Zhao, Jing Hua
AU - Isaacs, Aaron
AU - Wang, Lihua
AU - Luan, Jian’an
AU - Hwang, Shih Jen
AU - Mononen, Nina
AU - Auro, Kirsi
AU - Jackson, Anne U.
AU - Bielak, Lawrence F.
AU - Zeng, Linyao
AU - Shah, Nabi
AU - Nethander, Maria
AU - Campbell, Archie
AU - Rankinen, Tuomo
AU - Pechlivanis, Sonali
AU - Qi, Lu
AU - Zhao, Wei
AU - Rizzi, Federica
AU - Tanaka, Toshiko
AU - Robino, Antonietta
AU - Cocca, Massimiliano
AU - Lange, Leslie
AU - Müller-Nurasyid, Martina
AU - Roselli, Carolina
AU - Zhang, Weihua
AU - Kleber, Marcus E.
AU - Guo, Xiuqing
AU - Lin, Henry J.
AU - Pavani, Francesca
AU - Galesloot, Tessel E.
AU - Schunkert, Heribert
AU - Meitinger, Thomas
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85166440619
U2 - 10.1038/s41467-023-39521-2
DO - 10.1038/s41467-023-39521-2
M3 - Article
C2 - 37532724
AN - SCOPUS:85166440619
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4646
ER -
SDG 3 Good Health and Well-being