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Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Abstract

Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10−8); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality. We observed that a genetically predicted resting heart rate increase of 5 beats per minute was associated with a 20% increase in mortality risk (hazard ratio 1.20, 95% confidence interval 1.11–1.28, P = 8.20 × 10−7) translating to a reduction in life expectancy of 2.9 years for males and 2.6 years for females. Our findings provide evidence for shared genetic predictors of resting heart rate and all-cause mortality.

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Figure 1: Genome-wide −log10(P) plot and effects for significant loci.
Figure 2: Biological insights.

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Acknowledgements

This research was conducted using the UK Biobank Resource. This project is supported by the Netherlands organization for health research and development (ZonMw grant 90.700.441). S.B. is supported by the Wellcome Trust (grant 100114). P.B.M. acknowledges support from the NIHR Cardiovascular Biomedical Research Unit at Barts and the London School of Medicine and Dentistry, Queen Mary University of London. N.V. is supported by Netherlands Heart Institute and Marie Sklodowska-Curie Global Fellowship (grant 661395).

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Contributions

Participant recruitment, characterization and data generation: D.A.H., K.S., D.F.G., D.J.v.V., P.v.d.H. Data quality control and analysis: R.N.E., Y.H., D.A.H., K.S., D.F.G., R.N.E., N.V., P.v.d.H. Statistical analysis review: R.N.E., S.B., D.F.G., P.B.M., N.V., P.v.d.H. Central data analysis: R.N.E., Y.H., N.V. Supervision of the project: P.v.d.H. Draft of first version of the manuscript: R.N.E., P.v.d.H. All authors critically reviewed and approved the final version of the manuscript.

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Correspondence to Pim van der Harst.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10 and Supplementary Note (PDF 2582 kb)

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Supplementary Tables 1–15 (XLSX 236 kb)

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Eppinga, R., Hagemeijer, Y., Burgess, S. et al. Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality. Nat Genet 48, 1557–1563 (2016). https://doi.org/10.1038/ng.3708

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