title: 52 Genetic Loci Influencing Myocardial Mass.
abstract: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.
  
  
  
  This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.
  
  
  
  We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.
  
  
  
  We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.
  
  
  
  Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands. Electronic address: p.van.der.harst@umcg.nl.
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authors.affiliation: Institute of Medical Informatics, Biometry and Epidemiology, Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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authors.affiliation: Queensland Brain Institute, University of Queensland, St. Lucia, Australia; University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Australia.
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authors.lastname: Visscher
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.affiliation: DZHK partner site, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany).
authors.forename: Christian X
authors.initials: CX
authors.lastname: Weichenberger
authors.affiliation: Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.affiliation: Queensland Brain Institute, University of Queensland, St. Lucia, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Experimental Cardiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Biomedical Research Unit, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Boyer
authors.affiliation: Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Departments of Medicine, Epidemiology, and Health Services, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy; IRCCS Neuromed, Isernia, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciullo
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland; Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste, Italy; University of Trieste, Trieste, Italy; Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.affiliation: Icelandic Heart Association, Kópavogur, Iceland; University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK partner site, Greifswald, Germany.
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (Affiliated Institute of the University of Lübeck, Lübeck, Germany).
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; Ealing Hospital NHS Trust, Middlesex, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.affiliation: Cardiogenetics Lab, Human Genetics Research Centre, St. George's University of London, London, United Kingdom.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California; DOE Joint Genome Institute, Walnut Creek, California; School of Natural Sciences, University of California, Merced, California.
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.affiliation: Department of Anatomy, Embryology and Physiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology, Department of Biochemistry, Maastricht University, Maastricht, the Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Paul I W
authors.initials: PIW
authors.lastname: de Bakker
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans
keywords: QRS; electrocardiogram; genetic association study; heart failure; left ventricular hypertrophy