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Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders

Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

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Figure 1: Manhattan plot of SNPs after meta-analysis of stage 1.
Figure 2: Effect size as a function of effect allele frequency.
Figure 3: Combined effect of heart rate–increasing alleles on heart rate.
Figure 4: Effects on heart rate of reduced or ablated expression of orthologs of positional candidate genes from GWAS in D. melanogaster and D. rerio.

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Acknowledgements

A full list of acknowledgments appears in the Supplementary Note. Funding sources had no involvement in the collection, analysis and interpretation of the data.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

Steering committee (oversaw the project): M. den Hoed (lead) and R.J.F.L. (chair). Writing group (drafted the manuscript): M.E., M. den Hoed (chair), R.J.F.L. and N.J.S. Editing group (edited the manuscript): B.J.J.M.B., P.T.E., T.E., D.M.E., E.J.C.d.G., M. den Hoed (chair), E.I., D.J.M., R.J.F.L., A.L., D.J.M., I.M.N., A.V. Segrè, O.C.M.S., H.S., J.R.T. and N.J.T. Meta-analysis working group (performed stage 1 and stage 2 meta-analyses): T.E. and M. den Hoed (chair). Data preparation working group (prepared data from contributing cohorts for meta-analyses): M.E., T.E., M. den Hoed (lead) and R.J.F.L. (chair). Conditional analyses: M. den Hoed, R.J.F.L., P.M.V. (chair) and J.Y. (lead). Genetic predisposition score analyses: D.M.E., M. den Hoed (chair) and I.M.N. Association analyses with related traits: C.M.A., P.I.W.d.B., CARDIoGRAM Consortium, CHARGE-AF Consortium, Y.S.C., M.C., D.D., P.T.E., J. Erdmann, Global BPgen Consortium, M.J.G., M. den Hoed (chair), H.H., A.I., T.J., S. Kääb, Y.J.K., K.L.L., P.B.M., C.N.-C., A. Pfeufer, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, N.J.S., S. Sharp, N. Sotoodehnia and J.R.T. Copy number variant analyses: R.E.H. (lead), M. den Hoed (chair), S.A.M. and C. Stewart. Gene eQTL analyses: L. Franke (chair), M. den Hoed and H.-J.W. (lead). Proteomics experiments and genetic enrichment analyses: M. den Hoed, R.J.F.L., A.L. (lead), E.J.R. and J.V.O. (chair). SNIPPER analyses for selection of positional candidate genes: M. den Hoed (chair), R.J.F.L. and C. Willer (lead). Pathway analyses: M. den Hoed (chair), R.J.F.L. and A.V. Segrè (lead). D. melanogaster experiments: B.J.J.M.B. (lead), M. den Hoed, F.H.-B., B.K., R.J.F.L., O.C.M.S. (chair) and H.S. D. rerio experiments: M. den Hoed, R.J.F.L., S.N.L., D.J.M. (chair), D.S.P. (lead) and J.T.S.

Project design, management and coordination of contributing cohorts

Stage 1–GWAS: (ADVANCE) T.L.A., C.I. and T.Q.; (ALSPAC) G.D.S.; (ASCOT cases) N.R.P., P.S.S., D.C.S. and A.V. Stanton; (ATBC) D. Albanes and J. Virtamo; (B58C) W.L.M.C. and D.P.S.; (BLSA) S. Bandinelli and L. Ferrucci; (BRIGHT) M.C., T.J., P.B.M. and N.J.S.; (CoLaus) J.S.B., P.V. and G. Waeber; (COROGENE) M.-L.L.L., M.S.N., M.P. and J.S.; (deCODE) D.O.A., K.S. and U.T.; (DGI) L.G. and B.I.; (EGCUT) A.M.; (EPIC-Norfolk) N.J.W.; (Fenland) U.E., N.G.F., R.J.F.L. and N.J.W.; (Fingesture) H.V.H., J.D.R. and J.-C.T.; (Finrisk07) M.P. and V.S.; (FUSION) M. Boehnke and J.T.; (GOOD) C.O.; (HAPI) B.D.M. and A.R.S.; (HBCS) J. Eriksson, M.P. and E.W.; (Health 2000) A.J. and M.P.; (Health ABC) W.-C.H.; (HERITAGE) C. Bouchard, T.R. and D.C.R.; (HPFS) G.C., F.B.H., D.J.H., P.K., L.Q. and E.B.R.; (Hypergenes) D.C., N.G., L.I. and F.R.; (InCHIANTI) S. Bandinelli and L. Ferrucci; (Korcula) I.R.; (LifeLines) R.A.d.B., M.M.v.d.K., H.S. and R.P.S.; (Lolipop) J.C.C. and J.S.K.; (NBS) J.d.G. and L.A.K.; (NFBC1966) M.-R.J.; (NHS) G.C., F.B.H., D.J.H., P.K., L.Q. and E.B.R.; (NSPHS) U.G.; (PREVEND) W.H.v.G., G.N. and D.J.v.V.; (SPLIT) I.R.; and (YFS) M. Kähönen, T.L., M.P., O.T.R. and J. Viikari. Stage 2– in silico replication studies: (AGES, RRgen) V.G. and T.B.H.; (ACTS) N.G.M.; (ALSPAC) G.D.S.; (ARIC, RRgen) A.A.; (CHS, RRgen) B.M.P.; (DESIR) N.B.-N.; (EGCUT) A.M.; (Ely) N.J.W.; (EPIC-NL) J.M.A.B., Y.T.v.d.S. and W.M.M.V.; (EPIC-Norfolk) N.J.W.; (ERF) C.M.v.D. and B.A.O.; (FamHS) I.B.B.; (Fenland) U.E., N.G.F., R.J.F.L. and N.J.W.; (FHS, RRgen) C.J.O.; (Finrisk07) M.P. and V.S.; (KORA, RRgen) A. Peters and S. Kääb; (LifeLines2) R.A.d.B., M.M.v.d.K., H.S. and R.P.S.; (MESA) R.A.K. and J.I.R.; (MICROS, RRgen) P.P.P.; (NSHD) D.K.; (NTR) D.I.B. and E.J.C.d.G.; (ORCADES, RRgen) J.F.W.; (RISC) M.W.; (PIVUS) E.I. and L.L.; (RS1-3) A. Hofman, B.H.Ch.S. and J.C.M.W.; (SardiNIA, RRgen) E.G.L. and K.V.T.; (SHIP, RRgen) M.D. and S.B.F.; (Stanford IST) T.Q.; (STR) E.I. and N.L.P.; (Twins UK, RRgen) Y.J. and T.D.S.; (ULSAM) E.I.; and (Whitehall II) A. Hingorani and M. Kivimaki.

Genotyping of contributing cohorts

Stage 1–GWAS: (ADVANCE) D. Absher; (ALSPAC) S.M.R. and W.L.M.; (ATBC) S.J.C.; (BLSA) L. Ferrucci and A.B.S.; (BRIGHT) M.C. and P.B.M.; (COROGENE) P.S.; (EGCUT) T.E., L.M. and M.N.; (EPIC-Norfolk) R.J.F.L. and J.H.Z.; (Fenland) J.L.; (Fingesture) P.G. and J.D.R.; (Finrisk07) P.S.; (FUSION) P.S.C.; (GOOD) M. Lorentzon and C.O.; (HBCS) P.S.; (Health2000) P.L. and P.S.; (Health ABC) Y.L.; (HERITAGE) C. Bouchard and T.R.; (HPFS) M.C.C. and M.K.J.; (Hypergenes) C. Barlassina and P.B.; (InCHIANTI) L. Ferrucci and A.B.S.; (Korcula) C.H.; (LifeLines) L. Franke; (Lolipop) J.C.C. and J.S.K.; (NBS) L.A.K.; (NFBC1966) P.E., A.-L.H., M.-R.J. and P.Z.; (NHS) M.C.C. and M.K.J.; (NSPHS) Å.J.; (PREVEND) P.v.d.H.; (SPLIT) C.H. and V.V.; and (YFS) M. Kähönen, T.L., M.P., O.T.R., P.S. and J. Viikari. Stage 2– in silico replication studies: (ACTS) N.G.M., S.E.M. and G.W.M.; (ALSPAC) S.M.R. and W.L.M.; (ARIC, RRgen) D.E.A.; (DESIR) N.B.-N.; (EGCUT) T.E., L.M. and M.N.; (EPIC-NL) N.C.O.-M. and C. Wijmenga; (ERF) C.M.v.D., A.I. and B.A.O.; (Ely) R.J.F.L. and J.L.; (EPIC-Norfolk) R.J.F.L. and J.H.Z.; (FamHS) I.B.B. and M.F.F.; (Fenland) J.L.; (Finrisk07) P.S.; (LifeLines2) L. Franke; (MESA) J.I.R.; (NSHD) D.K., K.K.O. and A.W.; (NTR) D.I.B. and J.-J.H.; (PIVUS) E.I. and L.L.; (RS1-3) A.G.U.; (Stanford IST) T.L.A. and J.W.K.; (STR) E.I. and N.L.P.; (ULSAM) E.I.; and (Whitehall II) M. Kumari and C. Langenberg.

Phenotyping of contributing cohorts

Stage 1–GWAS: (ADVANCE) C.I.; (ASCOT cases) N.R.P., P.S.S. and A.V. Stanton; (ATBC) D. Albanes and J. Virtamo; (B58C) D.P.S.; (BLSA) S. Bandinelli and L. Ferrucci; (BRIGHT) M.C. and N.J.S.; (CoLaus) P.M.-V.; (COROGENE) M.P.; (deCODE) D.O.A. and H.H.; (DGI) B.I.; (EGCUT) K.F. and A.M.; (EPIC-Norfolk) K.-T.K.; (Fingesture) H.V.H. and J.J.; (Finrisk07) M.P.; (FUSION) H.M.S.; (GOOD) M. Lorentzon, C.O. and L.V.; (HBCS) J. Eriksson, M.P. and E.W.; (Health2000) A.J. and M.P.; (Health ABC) A.B.N.; (HERITAGE) C. Bouchard; (Hypergenes) D.C., N.G., L.I. and F.R.; (InCHIANTI) S. Bandinelli and L. Ferrucci; (Korcula) O.P.; (LifeLines) R.A.d.B., M.M.v.d.K. and R.P.S.; (Lolipop) J.C.C., A.S.K., J.S.K., K.A.M. and J.S.S.; (NBS) S.H.; (NFBC1966) A.-L.H., M.-R.J., A. Pouta and P.Z.; (PREVEND) R.A.d.B., W.H.v.G. and P.v.d.H.; (SPLIT) D.R.; and (YFS) M. Kähönen, T.L., M.P., O.T.R., P.S. and J. Viikari. Stage 2– in silico replication studies: (AGES, RRgen) V.G.; (ACTS) N.G.M. and J.B.W.; (CHS, RRgen) N. Sotoodehnia; (DESIR) B.B. and P.F.; (EGCUT) K.F. and A.M.; (Ely) S. Brage and U.E.; (EPIC-NL) J.M.A.B., Y.T.v.d.S. and W.M.M.V.; (EPIC-Norfolk) K.-T.K.; (ERF) C.M.v.D., A.I., J.A.K. and B.A.O.; (FamHS) I.B.B. and M.F.F.; (FHA, RRgen) C.N.-C.; (Finrisk07) M.P.; (LifeLines2) R.A.d.B., M.M.v.d.K. and R.P.S.; (MESA) S.R.H. and R.A.K.; (MICROS, RRgen) A.A.H.; (NSHD) D.K.; (NTR) D.I.B., E.J.C.d.G. and G. Willemsen; (ORCADES, RRgen) S.H.W.; (PIVUS) E.I. and L.L.; (RISC) M.W.; (RS1-3) B.H.Ch.S. and A.G.U.; (SHIP, RRgen) M.D. and M.R.P.M.; (Stanford IST) T.L.A. and J.W.K.; (STR) E.I. and N.L.P.; (ULSAM) E.I.; and (Whitehall II) M. Kumari.

Analyses of contributing cohorts

Stage 1–GWAS: (ADVANCE) T.L.A. and L.W.; (ALSPAC) D.M.E., J.P.K., B.S.P. and N.J.T.; (ASCOT cases) T.J.; (ATBC) W.W.; (B58C) D.H. and D.P.S.; (BLSA) T.T.; (BRIGHT) T.J. and S.P.; (CoLaus) M. Bochud and Z.K.; (COROGENE) P.S.; (deCODE) D.G. and H.H.; (DGI) P.A., C. Ladenvall and R.A.S.; (EGCUT) T.E. and E.M.; (EPIC-Norfolk) M. den Hoed, R.N.L. and J.H.Z.; (Fenland) M. den Hoed and J.L.; (Fingesture) G.B. and P.G.; (Finrisk07) A.S.H., K.K. and P.S.; (FUSION) A.U.J.; (GOOD) M. Lorentzon, C.O. and L.V.; (HAPI) M.E.M. and J.R.O.; (HBCS,) P.S.; (Health2000) P.S.; (Health ABC) W.-C.H. and O.T.N.; (HERITAGE) C. Bouchard, T.R. and D.C.R.; (HPFS) M.C.C. (InCHIANTI) T.T.; (Korcula) C.H.; (LifeLines) I.M.N. and H.S.; (Lolipop) J.C.C., J.S.K., J.S.S. and W.Z.; (NBS) M. den Heijer; (NFBC1966) P.F.O.; (NHS) M.C.C.; (Hypergenes) D.C.; (NSPHS) W.I.; (PREVEND) P.v.d.H. and I.M.L.; (SPLIT) C.H. and V.V.; and (YFS) P.S. Stage 2– in silico replication studies: (AGES, RRgen) A.V. Smith; (ACTS) P.A.L.; (ALSPAC) D.M.E., J.P.K., B.S.P. and N.J.T.; (ARIC, RRgen) A.C.M.; (CHS, RRgen) J.C.B. and N. Sotoodehnia; (DESIR) C.D., N.B.-N. and L.Y.; (EGCUT) T.E. and E.M.; (Ely) M. den Hoed and J.L.; (EPIC-NL) M. Leusink and N.C.O.-M.; (EPIC-Norfolk) M. den Hoed, R.N.L. and J.H.Z.; (ERF) A.I.; (FamHS) M.F.F. and S. Ketkar; (Fenland) M. den Hoed and J.L.; (FHS, RRgen) C.N.-C. and S.-J.H.; (Finrisk07) A.S.H. and K.K., P.S.; (KORA, RRgen) M.M.-N.; (LifeLines2) I.M.N. and H.S.; (MESA) K.F.K. and Q.W.; (MICROS, RRgen) C.F.; (NSHD) M. den Hoed, J.L. and A.W.; (NTR) H.H.M.D. and J.-J.H.; (ORCADES, RRgen) P.N.; (PIVUS) E.I. and C. Song; (RISC) M.N.W. and W.X.; (RRgen) P.I.W.d.B.; (RS1-3) P.I.W.d.B. and M.E.; (SardiNIA, RRgen) S. Sanna; (Stanford IST) W.X.; (STR) E.I. and C. Song; (Twins UK, RRgen) N. Soranzo; (ULSAM) E.I. and C. Song; and (Whitehall II) M. den Hoed and J.L.

The corresponding author (R.J.F.L.) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Ruth J F Loos.

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N.R.P. and A.V. Stanton have received financial support from several pharmaceutical companies that manufacture either blood pressure–lowering or lipid-lowering agents or both for consultancy fees, research projects and staff and for arranging and speaking at educational meetings. They do not hold stock or shares in any such companies. The authors that are affiliated with deCODE Genetics (H.H., D.G., U.T. and K.S.) are all employees of deCODE, a biotechnology company that provides genetic testing services, and some own stock or stock options in the company. F.H.-B. is an employee of Nyken, which holds intellectual property interests in heat shock protein expression as a treatment for atrial fibrillation. F.H.-B. does not hold stock or shares in Nyken. None of the other authors disclose competing financial interests.

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A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

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Supplementary Figures 1–7, Supplementary Tables 1–30 and Supplementary Note (PDF 2831 kb)

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den Hoed, M., Eijgelsheim, M., Esko, T. et al. Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet 45, 621–631 (2013). https://doi.org/10.1038/ng.2610

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