Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-07-17

AUTHORS

Bram P. Prins, Timothy J. Mead, Jennifer A. Brody, Gardar Sveinbjornsson, Ioanna Ntalla, Nathan A. Bihlmeyer, Marten van den Berg, Jette Bork-Jensen, Stefania Cappellani, Stefan Van Duijvenboden, Nikolai T. Klena, George C. Gabriel, Xiaoqin Liu, Cagri Gulec, Niels Grarup, Jeffrey Haessler, Leanne M. Hall, Annamaria Iorio, Aaron Isaacs, Ruifang Li-Gao, Honghuang Lin, Ching-Ti Liu, Leo-Pekka Lyytikäinen, Jonathan Marten, Hao Mei, Martina Müller-Nurasyid, Michele Orini, Sandosh Padmanabhan, Farid Radmanesh, Julia Ramirez, Antonietta Robino, Molly Schwartz, Jessica van Setten, Albert V. Smith, Niek Verweij, Helen R. Warren, Stefan Weiss, Alvaro Alonso, David O. Arnar, Michiel L. Bots, Rudolf A. de Boer, Anna F. Dominiczak, Mark Eijgelsheim, Patrick T. Ellinor, Xiuqing Guo, Stephan B. Felix, Tamara B. Harris, Caroline Hayward, Susan R. Heckbert, Paul L. Huang, J. W. Jukema, Mika Kähönen, Jan A. Kors, Pier D. Lambiase, Lenore J. Launer, Man Li, Allan Linneberg, Christopher P. Nelson, Oluf Pedersen, Marco Perez, Annette Peters, Ozren Polasek, Bruce M. Psaty, Olli T. Raitakari, Kenneth M. Rice, Jerome I. Rotter, Moritz F. Sinner, Elsayed Z. Soliman, Tim D. Spector, Konstantin Strauch, Unnur Thorsteinsdottir, Andrew Tinker, Stella Trompet, André Uitterlinden, Ilonca Vaartjes, Peter van der Meer, Uwe Völker, Henry Völzke, Melanie Waldenberger, James G. Wilson, Zhijun Xie, Folkert W. Asselbergs, Marcus Dörr, Cornelia M. van Duijn, Paolo Gasparini, Daniel F. Gudbjartsson, Vilmundur Gudnason, Torben Hansen, Stefan Kääb, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Henry J. Lin, Steven A. Lubitz, Dennis O. Mook-Kanamori, Francesco J. Conti, Christopher H. Newton-Cheh, Jonathan Rosand, Igor Rudan, Nilesh J. Samani, Gianfranco Sinagra, Blair H. Smith, Hilma Holm, Bruno H. Stricker, Sheila Ulivi, Nona Sotoodehnia, Suneel S. Apte, Pim van der Harst, Kari Stefansson, Patricia B. Munroe, Dan E. Arking, Cecilia W. Lo, Yalda Jamshidi

ABSTRACT

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes. More... »

PAGES

87

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  • Journal

    TITLE

    Genome Biology

    ISSUE

    1

    VOLUME

    19

    Author Affiliations

  • Department of Public Health and Primary Care, MRC/BHF Cardiovascular Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Worts’ Causeway, Cambridge, CB1 8RN UK
  • Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195 USA
  • Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98101 USA
  • CODE genetics/Amgen, Inc., 101 Reykjavik, Iceland
  • NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ UK
  • Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
  • Department of Medical Informatics Erasmus MC - University Medical Center, P.O. Box 2040, Rotterdam, 3000 CA The Netherlands
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
  • Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, 34137 Trieste, Italy
  • Institute of Cardiovascular Science, University College London, London, WC1E 6BT UK
  • Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201 USA
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA
  • Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP UK
  • Cardiovascular Department, Ospedali Riuniti and University of Trieste, 34100 Trieste, Italy
  • Department of Epidemiology, Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands
  • Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300RC The Netherlands
  • Department of Medicine, Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118 USA
  • Biostatistics Department, Boston University School of Public Health, Boston, MA 02118 USA
  • Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, University of Tampere, 33014 Tampere, Finland
  • Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU UK
  • Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, MS 39216 USA
  • German Centre for Cardiovascular Research (DZHK); partner site: Munich Heart Alliance, Munich, Germany
  • Barts Heart Centre, St Bartholomews Hospital, London, EC1A 7BE UK
  • Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, Glasgow, G12 8TA UK
  • Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142 USA
  • Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
  • Department of Cardiology, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
  • Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 2114.0 USA
  • DZHK (German Centre for Cardiovascular Research); Partner site Greifswald, 17475 Greifswald, Germany
  • Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322 USA
  • Department of Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
  • University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  • Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA The Netherlands
  • Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02114 USA
  • Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502 USA
  • Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
  • Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892 USA
  • Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, WA 98101 USA
  • Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands
  • Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, 33014 Tampere, Finland
  • Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84109 USA
  • Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200.0 Copenhagen, Denmark
  • Division of Cardiovascular Medicine, Stanford University, Stanford, CA 94305 USA
  • German Center for Diabetes Research, Neuherberg, Germany
  • Faculty of Medicine, University of Split, Split, Croatia
  • Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101 USA
  • Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20014 Turku, Finland
  • Department of Biostatistics, University of Washington, Seattle, WA 98195 USA
  • The Institute for Translational Genomics and Population Sciences and Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502 USA
  • Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
  • Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
  • Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany
  • Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
  • Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300RC The Netherlands
  • Human Genotyping Facility Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA The Netherlands
  • Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
  • Research unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  • Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 USA
  • TCM Clinical Basis Institute, Zhejiang Chinese Medical University, Hangzhou, 310000 Zhejiang China
  • Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK
  • Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar
  • School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland
  • Laboratory of Experimental Cardiology, University of Copenhagen, 2200 Copenhagen, Denmark
  • Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, 90502 USA
  • Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300RC The Netherlands
  • Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK
  • Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114 USA
  • Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG UK
  • Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK
  • Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA The Netherlands
  • Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA 98101 USA
  • Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
  • Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, London, UK
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13059-018-1457-6

    DOI

    http://dx.doi.org/10.1186/s13059-018-1457-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1105524469

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30012220


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