Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-08

AUTHORS

Dan E. Arking, Sara L. Pulit, Lia Crotti, Pim van der Harst, Patricia B. Munroe, Tamara T. Koopmann, Nona Sotoodehnia, Elizabeth J. Rossin, Michael Morley, Xinchen Wang, Andrew D. Johnson, Alicia Lundby, Daníel F. Gudbjartsson, Peter A. Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V. Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M. Lahtinen, Ilja M. Nolte, Albert Vernon Smith, Joshua C. Bis, Aaron Isaacs, Stephen J. Newhouse, Daniel S. Evans, Wendy S. Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A. Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J. Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W. Morris, Åsa T. Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G. Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A. Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D. Kumar, Tamara B. Harris, Lenore J. Launer, Alan R. Shuldiner, Alvaro Alonso, Joel S. Bader, Georg Ehret, Hailiang Huang, W.H. Linda Kao, James B. Strait, Peter W. Macfarlane, Morris Brown, Mark J. Caulfield, Nilesh J. Samani, Florian Kronenberg, Johann Willeit, , , J. Gustav Smith, Karin H. Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R. Heckbert, Bruce M. Psaty, Jerome I. Rotter, Ivana Kolcic, Ozren Polašek, Alan F. Wright, Maura Griffin, Mark J. Daly, , David O. Arnar, Hilma Hólm, Unnur Thorsteinsdottir, , Joshua C. Denny, Dan M. Roden, Rebecca L. Zuvich, Valur Emilsson, Andrew S. Plump, Martin G. Larson, Christopher J. O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P. D'Adamo, Annamaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R. Cummings, Michael A. Nalls, Antti Jula, Kimmo K. Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M. Nöthen, HRGEN consortium, Marcel den Hoed, Ruth J.F. Loos, Dag S. Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F. Sinner, Melanie Waldenberger, Rudolf A. de Boer, Lude Franke, Pieter A. van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A.M. Wilde, Elijah R. Behr, Chrysoula Dalageorgou, John R. Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M. Hamilton, Stephen W. Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E. Moravec, Greco M. Fabiola Del, Christian Fuchsberger, Jeffrey R. O'Connell, Wai K. Lee, Graham C.M. Watt, Harry Campbell, Sarah H. Wild, Nour E. El Mokhtari, Norbert Frey, Folkert W. Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P. van den Berg, Dirk J. van Veldhuisen, Manolis Kellis, Bouwe P. Krijthe, Oscar H. Franco, Albert Hofman, Jan A. Kors, André G. Uitterlinden, Jacqueline C.M. Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A. Oostra, Gonçalo R. Abecasis, Edward G. Lakatta, Antonella Mulas, Marco Orrú, David Schlessinger, Manuela Uda, Marcello R.P. Markus, Uwe Völker, Harold Snieder, Timothy D. Spector, Johan Ärnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimaki, Mika Kähönen, Nina Mononen, Olli T. Raitakari, Jorma S. Viikari, Vera Adamkova, Stefan Kiechl, Maria Brion, Andrew N. Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F. Dominiczak, Fredrik Nyberg, Peter H. Whincup, Aroon Hingorani, Jean-Jacques Schott, Connie R. Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F. Wilson, Igor Rudan, Andre Franke, Thomas W. Mühleisen, Peter P. Pramstaller, Terho J. Lehtimäki, Andrew D. Paterson, Afshin Parsa, Yongmei Liu, Cornelia van Duijn, David S. Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B. Felix, Serena Sanna, Marylyn D. Ritchie, Bruno H. Stricker, Kari Stefansson, Laurie A. Boyer, Thomas P. Cappola, Jesper V. Olsen, Kasper Lage, Peter J. Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J. Ackerman, Arne Pfeufer, Paul I.W. de Bakker, Christopher Newton-Cheh

ABSTRACT

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. More... »

PAGES

826-836

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    8

    VOLUME

    46

    Author Affiliations

  • Johns Hopkins University
  • University Medical Center Utrecht
  • Policlinico San Matteo Fondazione
  • University Medical Center Groningen
  • Queen Mary University of London
  • Academic Medical Center
  • University of Washington
  • Harvard University
  • Massachusetts Institute of Technology
  • National Heart Lung and Blood Institute
  • University of Copenhagen
  • deCODE Genetics (Iceland)
  • Massachusetts General Hospital
  • Erasmus University Medical Center
  • Vanderbilt University
  • National Institute on Aging
  • German Centre for Cardiovascular Research
  • Helsinki University Central Hospital
  • University of Groningen
  • University of Iceland
  • California Pacific Medical Center
  • Ontario Institute for Cancer Research
  • University of Tampere
  • Kiel University
  • Western General Hospital
  • IRCCS Materno Infantile Burlo Garofolo
  • Mayo Clinic
  • Institut du Thorax
  • Uppsala University
  • University College London
  • University of Gothenburg
  • University of Glasgow
  • Martin Luther University Halle-Wittenberg
  • Cyprus University of Technology
  • University of Santiago de Compostela
  • Innsbruck Medical University
  • Institute of Clinical and Experimental Medicine
  • University of Manchester
  • Washington University in St. Louis
  • Baltimore VA Medical Center
  • University of Minnesota
  • Glasgow Royal Infirmary
  • University of Cambridge
  • Lund University
  • German Cancer Research Center
  • University of Greifswald
  • Casa Sollievo della Sofferenza
  • Harbor–UCLA Medical Center
  • University of Split
  • National University Hospital of Iceland
  • Icelandic Heart Association
  • Boston University
  • University of Trieste
  • National Institutes of Health
  • National Institute for Health and Welfare
  • University of Helsinki
  • University of Tartu
  • University of Basel
  • University of Bonn
  • Institute of Metabolic Science
  • Icahn School of Medicine at Mount Sinai
  • Helmholtz Zentrum München
  • Technical University Munich
  • St George's, University of London
  • Hospital for Sick Children
  • University of Michigan–Ann Arbor
  • University of Maryland, Baltimore
  • University of Edinburgh
  • University Hospital Schleswig-Holstein
  • Netherlands Consortium for Healthy Ageing
  • Institute of Genetic and Biomedical Research
  • King's College London
  • Dalarna University
  • University of Turku
  • AstraZeneca (Sweden)
  • Wellcome Centre for Human Genetics
  • Forschungszentrum Jülich
  • Ospedale di Bolzano
  • Pennsylvania State University
  • Istituto Auxologico Italiano
  • Institute of Bioinformatics and Systems Biology
  • Clinical Trials linked to this publication

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.3014

    DOI

    http://dx.doi.org/10.1038/ng.3014

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1004633015

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/24952745


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