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 of Groningen
Borbala Mifsud, Queen Mary University of London
Jeffrey Haessler, Fred Hutchinson Cancer Research Center
Nathan A Bihlmeyer, Johns Hopkins University School of Medicine
Yi-Ping Fu, National Heart, Lung, and Blood Institute
Stefan Weiss, University Medicine and Ernst-Moritz-Arndt-University Greifswald
Henry J Lin, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
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, Helmholtz Zentrum München - German Research Center for Environmental Health
Honghuang Lin, Boston University School of Medicine
Hao Mei, University of Mississippi Medical Center
Albert V Smith, Icelandic Heart Association
Leo-Pekka Lyytikäinen, Fimlab Laboratories and University of Tampere School of Medicine
Leanne M. Hall, University of Leicester
Jessica van Setten, University Medical Center Utrecht
Stella Trompet, Leiden University Medical Center
Bram P Prins, Wellcome Trust Sanger Institute
Aaron Isaacs, Maastricht University
Farid Radmanesh, Massachusetts General Hospital
Jonathan Marten, University of Edinburgh
Aiman Entwistle, Queen Mary University of London
Jan A Kors, University Medical Center Rotterdam
Claudia T Silva, Erasmus University Medical Center
Alvaro Alonso, Emory University
Joshua C Bis, University of Washington
Rudolf de Boer, University of Groningen
Hugoline G de Haan, Leiden University Medical Center,
Renée de Mutsert, Massachusetts General Hospital
George Dedoussis, Harokopio University
Anna F Dominiczak, University of Glasgow,
Alex S F Doney, University of Dundee
Patrick T Ellinor, Broad Institute
Ruben N Eppinga, University of Groningen
Stephan B Felix, University Medicine Greifswald
Xiuqing Guo, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Yanick Hagemeijer, University of Groningen
Torben Hansen, University of Copenhagen
Tamara B Harris, National Institute on Aging
Susan R Heckbert, University of Washington
Paul L Huang, Massachusetts General Hospital
Shih-Jen Hwang, National Heart, Lung, and Blood Institute
Mika Kähönen, Tampere University Hospital and University of Tampere School of Medicine
Jørgen K Kanters, University of Copenhagen
Ivana Kolcic, University of Split
Lenore J Launer, National Institutes of Health
Man Li, University of Utah
Jie Yao, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Allan Linneberg, Research Centre for Prevention and Health
Simin Liu, Brown University School of Public Health
Peter W Macfarlane, University of Glasgow
Massimo Mangino, King's College London
Andrew D Morris, University of Edinburgh
Antonella Mulas, Istituto di Ricerca Genetica e Biomedica (IRGB)
Alison D Murray, University of Aberdeen
Christopher P Nelson, University of Leicester
Marco Orrú, Presidio Ospedaliero Oncologico Armando Businco Cagliari
Sandosh Padmanabhan, University of Glasgow
Annette Peters, DZHK (German Centre for Cardiovascular Research)
David J Porteous, University of Edinburgh
Neil Poulter, Imperial College London
Bruce M Psaty, University of Washington
Lihong Qi, University of California Davis
Olli T Raitakari, University of Turku
Fernando Rivadeneira, Broad Institute of MIT and Harvard
Carolina Roselli, Broad Institute of MIT and Harvard
Igor Rudan, University of Edinburgh
Naveed Sattar, University of Glasgow,
Peter Sever, Imperial College London
Moritz F Sinner, DZHK (German Centre for Cardiovascular Research)
Elsayed Z Soliman, Wake Forest School of Medicine
Timothy D Spector, King's College London
Alice V. Stanton, Royal College of Surgeons in IrelandFollow
Kathleen E Stirrups, Queen Mary University of London
Kent D Taylor, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Martin D Tobin, University of Leicester
André Uitterlinden, University Medical Center Rotterdam
Ilonca Vaartjes, University Medical Center
Arno W Hoes, Helmholtz Zentrum München - German Research Center for Environmental Health
Peter van der Meer, University of Groningen
Uwe Völker, University Medicine and Ernst-Moritz-Arndt-University Greifswald
Melanie Waldenberger, Helmholtz Zentrum München - German Research Center for Environmental Health
Zhijun Xie, Boston University School of Medicine
Magdalena Zoledziewska, Istituto di Ricerca Genetica e Biomedica (IRGB)
Andrew Tinker, Queen Mary University of London
Ozren Polasek, University of Split
Jonathan Rosand, Center for Human Genetic Research
Yalda Jamshidi, University of London
Cornelia M van Duijn, Erasmus University Medical Center
Eleftheria Zeggini, Wellcome Trust Sanger Institute
J Wouter Jukema, Leiden University Medical Center
Folkert W Asselbergs, University Medical Center Utrecht
Nilesh J Samani, University of Leicester
Terho Lehtimäki, Fimlab Laboratories and University of Tampere School of Medicine
Vilmundur Gudnason, Icelandic Heart Association
James Wilson, University of Mississippi Medical Center
Steven A Lubitz, Broad Institute
Stefan Kääb, DZHK (German Centre for Cardiovascular Research)
Nona Sotoodehnia, University of Washington
Mark J Caulfield, Queen Mary University of London
Colin NA Palmer, University of Dundee
Serena Sanna, Istituto di Ricerca Genetica e Biomedica (IRGB)
Dennis O Mook-Kanamori, Leiden University Medical Center
Panos Deloukas, Queen Mary University of London
Oluf Pedersen, University of Copenhagen
Jerome I Rotter, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Marcus Dörr, University Medicine Greifswald
Chris J O'Donnell, Boston Veteran's Administration Healthcare
Caroline Hayward, University of Edinburgh
Dan E Arking, Johns Hopkins University School of Medicine
Charles Kooperberg, Fred Hutchinson Cancer Research Center
Pim van der Harst, University of Groningen
Mark Eijgelsheim, University Medical Center Rotterdam
Bruno H Stricker, University Medical Center Rotterdam
Patricia B Munroe, Queen Mary University of London

Peer Reviewed

1

Document Type

Article

Publication Date

15-6-2017

Keywords

Adult, Alleles, European Continental Ancestry Group, Exome, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Risk Factors

Comments

The original article is available at https://academic.oup.com/

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.

Disciplines

Life Sciences

Citation

van den Berg M, Warren HR, Cabrera CP, Verweij N, Mifsud B, Haessler J, et al. Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics. 2017; 26(12):2346-2363

PubMed ID

28379579

DOI Link

10.1093/hmg/ddx113.

Creative Commons License

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This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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