Identification of heart rate-associated loci and genes

doi:10.1038/protex.2013.041

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Identification of heart rate-associated loci and genes

https://doi.org/10.1038/protex.2013.041

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Elevated resting heart rate is associated with increased risk of cardiovascular disease and mortality. In a two-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 seven previously established loci. Experimental down-regulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes from 11 loci as 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 decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into mechanisms regulating heart rate and identify novel targets that may be modifiable for therapeutic benefit.

Genetics

Biological techniques

Heart rate

cardiovascular disease genome-wide association

GWA

GWAS

genetic epidemiology

ECG

atrial fibrillation

cardiac conduction

sick sinus syndrome

myocardial infarction

coronary artery disease

Danio rerio

zebrafish

Drosophila melanogaster

edema

blood pooling

unlooped heart

We designed a multistage study comprising a meta-analysis of genome wide association studies (GWAS) (stage 1) with data from up to 92,355 individuals from 36 studies and selected lead SNPs from 42 loci - the 12 loci that reached genome wide significance (p<5×10⁻⁸) after stage 1 and 30 additional loci with the lowest p-values for association that did not reach genome wide significance (p<3×10⁻⁵) - for follow up in stage 2 (Supplementary Figure 1). Stage 2 comprised data from up to 88,823 additional individuals from 37 studies. Meta-analysis of summary statistics from stage 1 and stage 2 identified variants in 21 loci that reached genome wide significance. For these loci we subsequently performed additional association analyses to examine their relevance for cardiovacular intermediates and disease, as well as functional follow-up experiments in animal models to identify potentially causal genes.

See the attachment 'Online Protocols' under the header 'Figures' for a description of the reagents used in our studies.

See the attachment 'Online Protocols' under the header 'Figures' for a description of the equipment used in our studies.

See the attachment 'Online Protocols' under the header 'Figures' for a description of the procedures used in our studies.

We kindly refer the reader to our original article entitled: 'Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders' for the results of the studies that are described in the attachment 'Online Protocols' under the header 'Figures'.

See the attachment 'Online Protocols' under the header 'Figures' for all references that are relevant for the protocols used in our studies.

All acknowledgments are provided in a dedicated section of the Supplementary Information that accompanies the original article.

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The corresponding author had no competing financial interests.

Neil Poulter and Alice Stanton have received financial support from several pharmaceutical companies which manufacture either BP-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 stocks or shares in any such companies.

The authors that are affiliated with deCODE genetics (Hilma Holm, Daniel Gudbjartsson, Unnur Thorsteinsdottir and Kari Stefansson) are all employees of deCODE, a biotechnology company that provides genetic testing services and some own stocks or stock options in the company.

Femke Hoogstra-Berends is an employee of Nyken BV, which holds intellectual property interests in heat shock protein expression as a treatment for AF. She does not hold stocks or shares in Nyken BV.

None of the remaining authors disclose a competing financial interest.

supplement0.pdf
Online Protocols Online Protocols All (Supplementary) Figures and Tables that we refer to in the Online Protocols can be found in the original article and accompanying Supplementary Information.

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Identification of heart rate-associated loci and genes

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Abstract

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Identification of heart rate-associated loci and genes

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Abstract

Figures

Introduction

Reagents

Equipment

Procedure

Anticipated Results

References

Acknowledgements

Additional Declarations

Supplementary Files

Associated Publications

Status:

Version 1

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Terms of Service

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