title: Discovery of novel heart rate-associated loci using the Exome Chip.
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.
authors.affiliation: Department of Medical Informatics Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
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authors.initials: ME
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authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics; University Medicine and Ernst-Moritz-Arndt-University Greifswald; Greifswald, 17475, Germany.|DZHK (German Centre for Cardiovascular Research); partner site Greifswald; Greifswald, 17475, Germany.
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authors.initials: JW
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authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
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authors.forename: Terho
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authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.|Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-Universität, Munich, Germany.
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authors.initials: S
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authors.affiliation: Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
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authors.affiliation: Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
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authors.initials: MJ
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authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, DD1?9SY, UK.
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authors.initials: CNA
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authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
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authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
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authors.initials: DO
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authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine; University Medicine Greifswald; Greifswald, 17475, Germany & DZHK (German Centre for Cardiovascular Research); partner site Greifswald; Greifswald, 17475, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dörr
authors.affiliation: Boston Veteran's Administration Healthcare, Boston MA, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4?2XU, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 21205 and.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: University Medical Center Groningen, University of Groningen, Department of Cardiology, the Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Eijgelsheim
authors.affiliation: Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
mesh_terms: D000328:Adult; D000483:Alleles; D059472:Exome; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006339:Heart Rate / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics