Discovery of novel heart rate-associated loci using the Exome Chip.

• Type of Material: Article
• Authors: Marten E. van den Berg, University Medical Center Rotterdam; Helen R. Warren, Queen Mary University of London; Claudia P. Cabrera, Queen Mary University of London; Niek Verweij, University Medical Center Groningen; Borbala Mifsud, Queen Mary University of London; Jeffrey Haessler, Fred Hutchinson Cancer Research Center; Nathan A. Bihlmeyer, Johns Hopkins University; Yi-Ping Fu, National Institutes of Health; Stefan Weiss, University Medicine and Ernst-Moritz-Arndt-University Greifswald; Henry J. Lin, Bioomedical Research Institute at Harbor-UCLA; Niels Grarup, University of Copenhagen; Ruifang Li-Gao, Leiden University Medical Center; Giorgio Pistis, Istituto di Ricerca Genetica e Biomedica (IRGB); Nabi Shah, University of Dundee; Jennifer A. Brody, University of Washington; Martina Müller-Nurasyid, German Research Center for Environmental Health; Honghuang Lin, Boston University; Hao Mei, University of Mississippi; Albert V. Smith, Icelandic Heart Association; Leo-Pekka Lyytikäinen, Fimlab Laboratories and University of Tampere; Alvaro Alonso, Emory University
• Language: English
• Date: 2017-06-15
• Publisher: Oxford University Press
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2017, Oxford University Press
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddx113
• Title of Journal or Parent Work: Human Molecular Genetics
• ISSN: 0964-6906
• Volume: 26
• Issue: 12
• Start Page: 2346
• End Page: 2363
• Grant/Funding Information: See publication for full funding statement.
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.