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

Funding Information: We thank all participants for their participation and valuable contributions. This research has been conducted using the UK Biobank Resource under application number 12010. The work of N.V. was supported by NWO VENI grant 016.186.125. We thank 23andMe and the 23andMe Research Team for their contribution sharing their data and performing the GWAS analysis in the 23andMe cohort. P.V. received an unrestricted grant from GlaxoSmithkline to build the CoLaus study. N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Program (C18281/A29019). A detailed list of acknowledgements and funding is provided in Supplementary Data per cohort. We also thank all individuals that contributed to the generation of software programs, algorithms and genetic summary statistics. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Authors involved in the funding of the cohorts are listed below. Meta-analyses, Lifelines, PREVEND, UK Biobank: P.v.d.H.; ADDITION-PRO: T.H.; ADVANCE: C.I.; ADVANCE: T.A.; AGES: L.Launer, V.G.; ASCOT: P.Sever, P.B.M.; BC1936: N.G.; BioMe: E.P.B., R.J.F.L.; BRIGHT: P.B.M.; CHS: B.M.P.; CoLaus: P.V.; Croatia-Korcula: O.P., C.H.; DCCT/EDIC: D.R., The DCCT/EDIC Research Group, A.D.P.; DESIR: B.B., P.F.; DGI: L.G.; EPIC-Norfolk: N.J.W.; ERF: C.M.v.D.; Fenland: N.J.W.; FINCAVAS: M.K.; Finrisk: M.P.; FUSION: M.B.; GENOA: P.A.P., S.L.R.K.; GerMIFSs: H.Schunkert, J.E.; GoDARTS: C.N.A.P; GOOD: M.L., C.O.; HBCS: J.G.E.; HERITAGE: T.R., D.C.R., C.B.; HPFS / NHS: P.K.; HRS: D.R.Weir; HYPERGENES: K.S.S., D.C.; InCHIANTI: S.Bandinelli, L.Ferrucci; INGI-CARL: M.P.C.; INGI-FVG: G.G.; JHS: A.Correa; KORA F3: T.M., S.K.; KORA S4: K.Strauch., A.P.; LOLIPOP: J.C.C., J.S.K.; LURIC: W.M.; MESA: J.I.R.; MICROS: A.H.; MPP: O.M.; J.G.S.; NBS: L.A.L.M.K.; NEO: R.d.M.; NESDA: B.W.J.H.P.; NSPHS: Å.J.; ORCADES: J.F.W.; PIVUS: L.L.; PROSPER: P.W.M., J.W.J.; SardiNIA: E.L.L.; SCES: C.Y.C.; SHIP: S.B.F., M.D.; SIMES: T.Y.W.; TRAILS: A.J.O.; TWINS: J.O.; ULSAM: A.P.M., C.Lindgren; YFS: O.T.R., T.L. Funding Information: We thank all participants for their participation and valuable contributions. This research has been conducted using the UK Biobank Resource under application number 12010. The work of N.V. was supported by NWO VENI grant 016.186.125. We thank 23andMe and the 23andMe Research Team for their contribution sharing their data and performing the GWAS analysis in the 23andMe cohort. P.V. received an unrestricted grant from GlaxoSmithkline to build the CoLaus study. N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Program (C18281/A29019). A detailed list of acknowledgements and funding is provided in Supplementary Data 1 per cohort. We also thank all individuals that contributed to the generation of software programs, algorithms and genetic summary statistics. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Authors involved in the funding of the cohorts are listed below. Meta-analyses, Lifelines, PREVEND, UK Biobank : P.v.d.H.; ADDITION-PRO : T.H.; ADVANCE : C.I.; ADVANCE : T.A.; AGES : L.Launer, V.G.; ASCOT : P.Sever, P.B.M.; BC1936 : N.G.; BioMe : E.P.B., R.J.F.L.; BRIGHT : P.B.M.; CHS : B.M.P.; CoLaus : P.V.; Croatia-Korcula : O.P., C.H.; DCCT/EDIC : D.R., The DCCT/EDIC Research Group, A.D.P.; DESIR : B.B., P.F.; DGI : L.G.; EPIC-Norfolk : N.J.W.; ERF : C.M.v.D.; Fenland : N.J.W.; FINCAVAS : M.K.; Finrisk : M.P.; FUSION : M.B.; GENOA : P.A.P., S.L.R.K.; GerMIFSs : H.Schunkert, J.E.; GoDARTS : C.N.A.P; GOOD : M.L., C.O.; HBCS : J.G.E.; HERITAGE : T.R., D.C.R., C.B.; HPFS / NHS: P.K.; HRS : D.R.Weir; HYPERGENES : K.S.S., D.C.; InCHIANTI : S.Bandinelli, L.Ferrucci; INGI-CARL: M.P.C.; INGI-FVG: G.G.; JHS: A.Correa; KORA F3: T.M., S.K.; KORA S4 : K.Strauch., A.P.; LOLIPOP : J.C.C., J.S.K.; LURIC : W.M.; MESA : J.I.R.; MICROS : A.H.; MPP : O.M.; J.G.S.; NBS : L.A.L.M.K.; NEO : R.d.M.; NESDA : B.W.J.H.P.; NSPHS : Å.J.; ORCADES : J.F.W.; PIVUS : L.L.; PROSPER : P.W.M., J.W.J.; SardiNIA : E.L.L.; SCES : C.Y.C.; SHIP : S.B.F., M.D.; SIMES : T.Y.W.; TRAILS : A.J.O.; TWINS : J.O.; ULSAM : A.P.M., C.Lindgren; YFS : O.T.R., T.L. Publisher Copyright: © 2023, The Author(s).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.Peer reviewe