Genetic insights into resting heart rate and its role in cardiovascular disease

The DCCT/EDIC Research Group

doi:10.1038/s41467-023-39521-2

Genetic insights into resting heart rate and its role in cardiovascular disease

The DCCT/EDIC Research Group

Department of Public Health - Department of Epidemiology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

9 Citations (Scopus)

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.

Original language	English
Article number	4646
Journal	Nature Communications
Volume	14
Issue	1
Number of pages	21
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-39521-2
Publication status	Published - Dec 2023

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title = "Genetic insights into resting heart rate and its role in cardiovascular disease",

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.",

author = "{van de Vegte}, {Yordi J.} and Eppinga, {Ruben N.} and {van der Ende}, {M. Yldau} and Hagemeijer, {Yanick P.} and Yuvaraj Mahendran and Elias Salfati and Smith, {Albert V.} and Tan, {Vanessa Y.} and Arking, {Dan E.} and Ioanna Ntalla and Appel, {Emil V.} and Claudia Schurmann and Brody, {Jennifer A.} and Rico Rueedi and Ozren Polasek and Gardar Sveinbjornsson and Cecile Lecoeur and Claes Ladenvall and Zhao, {Jing Hua} and Aaron Isaacs and Lihua Wang and Jian{\textquoteright}an Luan and Hwang, {Shih Jen} and Nina Mononen and Kirsi Auro and Jackson, {Anne U.} and Bielak, {Lawrence F.} and Linyao Zeng and Nabi Shah and Maria Nethander and Archie Campbell and Tuomo Rankinen and Sonali Pechlivanis and Lu Qi and Wei Zhao and Federica Rizzi and Toshiko Tanaka and Antonietta Robino and Massimiliano Cocca and Leslie Lange and Martina M{\"u}ller-Nurasyid and Carolina Roselli and Weihua Zhang and Kleber, {Marcus E.} and Xiuqing Guo and Lin, {Henry J.} and Francesca Pavani and Witte, {Daniel R.} and {The DCCT/EDIC Research Group}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

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doi = "10.1038/s41467-023-39521-2",

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T1 - Genetic insights into resting heart rate and its role in cardiovascular disease

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 - Witte, Daniel R.

AU - The DCCT/EDIC Research Group

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.

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DO - 10.1038/s41467-023-39521-2

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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ER -

Genetic insights into resting heart rate and its role in cardiovascular disease

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