Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.14279/3665
Title: Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
Authors: Arking, Dan E E. 
Pulit, Sara L. 
Crotti, Lia 
Van Der Harst, Pim 
Munroe, Patricia B. 
Koopmann, Tamara T. 
Sotoodehnia, Nona 
Rossin, Elizabeth J. 
Morley, Michael P. 
Wang, Xinchen 
Johnson, Andrew D. 
Roden, Dan M. 
Zuvich, Rebecca Lynn 
Emilsson, Valur 
Viikari, Jorma Sa A 
Plump, Andrew S. 
Larson, Martin G. 
Den Hoed, Marcel 
O'Donnell, Christopher J. 
Yin, Xiaoyan 
O'Connell, Jeffrey 
Sanna, Serena 
Bobbo, Marco 
d'Adamo, Adamo Pio 
Iorio, Annamaria M. 
Sinagra, Gianfranco F. 
Carracedo, Angel M. 
Adamkova, Vera 
Cummings, Steven Ron 
Nalls, Michael A. 
Jula, Antti M. 
Loos, Ruth JF F 
Ritchie, Marylyn D. 
Paulweber, Bernhard 
Thelle, Dag Steinar 
Gieger, Christian 
Meitinger, Thomas A. 
Perz, Siegfried 
Peters, Annette 
Prucha, Hanna 
Kiechl, Stefan G. 
Sinner, Moritz F. 
Waldenberger, Melanie 
Stricker, Bruno Ch Ch H 
Gudbjartsson, Daniel Fannar 
Kumar, Runjun D. 
De Boer, Rudolf A. 
Franke, Lude 
Van Der Vleuten, Pieter A. 
Beckmann, Britt Maria 
Martens, Eimo 
Bardai, Abdennasser 
Hofman, Nynke 
Brion, Maria Jose 
Perola, Markus 
Wilde, Arthur Arnold Maria 
Behr, Elijah Raphael 
Lee, Wai K. 
Dalageorgou, Chrysoula 
Noseworthy, Peter A. 
Giudicessi, John R. 
Medeiros-Domingo, Argelia 
Barc, Julien 
Kyndt, Florence 
Probst, Vincent 
Stefansson, Kari 
Ghidoni, Alice 
Nicolaides, Andrew N. 
Insolia, Roberto 
Watt, Graham Cm M 
Campbell, Harry 
Wild, Sarah H. 
El Mokhtari, Nour Eddine 
Bradford, Yuki 
Frey, Norbert 
Asselbergs, Folkert W. 
Boyer, Laurie A. 
Leach, Irene Mateo 
Navis, Gerjan J. 
Harris, Tamara B. 
Lahtinen, Annukka M. 
Van Den Berg, Maarten P. 
Van Veldhuisen, Dirk Jan 
Kellis, Manolis 
Krijthe, Bouwe P. 
Franco, Oscar H. 
Hofman, Albert 
Bis, Joshua C M 
Tarasov, Kirill V. 
Kors, Jan A. 
Uitterlinden, André Gerardus 
Launer, Lenore J. 
Witteman, Jacqueline C M 
Kontula, Kimmo K. 
Kedenko, Lyudmyla 
Lamina, Claudia 
Oostra, Ben A. 
Abecasis, Goncalo R. 
Cappola, Thomas P. 
Lakatta, Edward G. 
Mulas, Antonella 
Orru, Marco 
Dorr, Marcus 
Shuldiner, Alan R. 
Schlessinger, David 
Uda, Manuela 
Haerting, Johannes 
Markus, Marcello Ricardo Paulista 
Volker, Uwe U. 
Olsen, Jesper Velgaard 
Snieder, Harold 
Spector, Tim David 
Arnlov, Johan 
Lind, Lars 
Sundstrom, Johan 
Alonso, Álvaro 
Syvanen, Ann Christine 
Muller-Nurasyid, Martina 
Kivimaki, Mika 
Dominiczak, Anna F. 
Kao, Wenhong 
Nyberg, Fredrik 
Whincup, Peter H. 
Hingorani, Aroon D. 
Schott, Jean Jacques 
Bezzina, Connie R. 
Ingelsson, Erik 
Bader, Joel S. 
Ferrucci, Luigi 
Gasparini, Paolo 
Marjamaa, Annukka 
Hamilton, Robert Murray 
Nolte, Ilja Maria 
Wilson, James F. 
Rudan, Igor 
Franke, Andre 
Muhleisen, Thomas Walter Alter 
Pramstaller, Peter P. 
Lehtimaki, Terho J. 
Ehret, Georg B. 
Paterson, Andrew D. 
Parsa, Afshin 
Lage, Kasper 
Liu, Yongmei 
Oikarinen, Lasse 
Van Duijn, Cornelia M. 
Smith, Albert Vernon Ernon 
Siscovick, David S. 
Gudnason, Vilmundur G. 
Jamshidi, Yalda 
Salomaa, Veikko V. 
Huang, Hailiang 
Felix, Stephan Burkhart Urkhart 
Schwartz, Peter John 
Kaab, Stefan 
Chakravarti, Aravinda H. 
Ackerman, Michael John 
Porthan, Kimmo 
Pfeufer, Arne 
De Bakker, Paul IW W 
Newton-Cheh, Christopher 
Isaacs, Aaron J. 
Scherer, Stephen Wayne 
Kalsch, Hagen I M 
Newhouse, Stephen J. 
Evans, Daniel S. 
Post, Wendy S. 
Waggott, Daryl R. 
Lyytikainen, Leo Pekka 
Hicks, Andrew Antony 
Erbel, Raimund M. 
Eisele, Lewin 
Ellinghaus, David 
Brandimarto, Jeffrey 
Hayward, Caroline 
Kahonen, Mika 
Navarro, Pau 
Ulivi, Sheila 
Tanaka, Toshiko 
Tester, David J. 
Chatel, Stephanie 
Gustafsson, Stefan E. 
Kumari, Meena 
Hoffmann, Per 
Eijgelsheim, Mark 
Morris, Richard W. 
Naluai, Asa Torinsson 
Strait, James B. 
Padmanabhan, Sandosh 
Kluttig, Alexander 
Strohmer, Bernhard 
Panayiotou, Andrie 
Torres, Maria Cruz 
Knoflach, Michael 
Hubacek, Jaroslav Alois 
Margulies, Kenneth B. 
Slowikowski, Kamil 
Jockel, Karl Heinz 
Raychaudhuri, Soumya 
MacFarlane, Peter W. 
Brown, Morris J. 
Caulfield, Mark J. 
Samani, Nilesh J. 
Kronenberg, Florian 
Willeit, Johann 
Smith, Jarrett Gustav 
Moravec, Christine E. 
Greiser, Karin Halina 
Zu Schwabedissen, Henriette Meyer 
Mononen, Nina 
Nothen, Markus M. 
Werdan, Karl 
Carella, Massimo 
Zelante, Leopoldo L. 
Heckbert, Susan R. 
Psaty, Bruce M. 
Rotter, Jerome I. 
Del Greco M., Fabiola 
Kolcic, Ivana 
Polasek, Ozren 
Wright, Alan F. 
Raitakari, Olli T. 
Griffin, Maura B. 
Lundby, Alicia 
Daly, Mark J. 
Arnar, David O 
Holm, Hilma A. 
Thorsteinsdottir, Unnur 
Fuchsberger, Christian 
Denny, Joshua C. 
Major Field of Science: Medical and Health Sciences
Field Category: Clinical Medicine
Keywords: Calcium signaling;Cardiovascular risk;Controlled study;Gene expression;Genetic association;Genetic variability;Heart electrophysiology;Heart ventricle arrhythmia
Issue Date: Aug-2014
Source: Nature Genetics, 2014, Volume 46, Issue 8, Pages 826-836
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.
URI: https://hdl.handle.net/20.500.14279/3665
ISSN: 15461718
DOI: 10.1038/ng.3014
Rights: © Nature America, Inc.
Type: Article
Affiliation : Johns Hopkins University 
Massachusetts General Hospital 
University Medical Center Utrecht 
University of Pavia 
Istituto Auxologico Italiano 
Institute of Harvard and MIT 
University of Groningen 
Queen Mary University of London 
University of Washington 
Netherlands Consortium for Healthy Aging 
Casa Sollievo della Sofferenza 
University Medicine Greifswald 
German Center for Cardiovascular Research 
Ludwig Maximilians University 
German Research Center for Environmental Health 
University of Groningen 
Icelandic Heart Association 
University of Iceland 
Erasmus University Rotterdam 
California Pacific Medical Center Research Institute 
Ontario Institute for Cancer Research 
Institute for Maternal and Child Health 
University of Tampere 
Center for Biomedicine 
University Duisburg-Essen 
University of Kiel 
Western General Hospital 
Mayo Clinic 
Université de Nantes 
Karolinska Institutet 
Uppsala University 
University College London 
University of Gothenburg 
Biobanking and Molecular Resource Infrastructure of Sweden 
University of Glasgow 
Martin Luther University Halle-Wittenberg 
Institute for Clinical and Experimental Medicine 
Paracelsus Medical University 
Cyprus University of Technology 
Cyprus Cardiovascular Disease and Educational Research Trust 
Universidade de Santiago de Compostela 
Innsbruck Medical University 
Partners HealthCare Center for Personalized Genetic Medicine 
Brigham and Women's Hospital 
The University of Manchester 
Washington University 
University of Maryland 
Veterans Administration Medical Center 
University of Minnesota 
University of Cambridge 
Group Health Cooperative 
University of Leicester 
Innsbruck Medical University 
Lund University 
German Cancer Research Center 
University of Greifswald 
University Halle-Wittenberg 
Harbor-University of California 
University of Split 
Vascular Screening and Diagnostic Center 
Landspítali University Hospital 
Sanofi Research and Development 
Boston University 
University of Trieste 
Servicio Galego de Saude 
Addenbrooke's Hospital 
King Abdulaziz University 
US National Institutes of Health 
National Institute for Health and Welfare 
University of Helsinki 
University of Tartu 
University of Bonn 
University of Basel 
Mindich Child Health and Development Institute 
University of Oslo 
Technische Universität München 
Christine Kühne-Center for Allergy and Education 
Hospital of Friedberg 
Academic Medical Centre 
Centre of Excellence in Research of Hereditary Disorders 
St George's University of London 
Hospital for Sick Children Research Institute 
CNR - National Research Council of Italy 
University of Michigan 
University of Glasgow 
The University of Edinburgh 
University of Kiel 
Interuniversity Cardiology Institute of the Netherlands 
University Medical Center Utrecht 
University Medical Center Groningen 
Ernst Moritz Arndt University Greifswald 
King's College London 
Dalarna University 
Turku University Hospital 
University of Turku 
AstraZeneca Research and Development 
University of Oxford 
Research Centre Juelich 
Harvard University 
University of Lübeck 
General Central Hospital 
Hospital for Sick Children Research Institute 
Wake Forest University 
Pennsylvania State University 
Inspectorate of Health Care 
Technical University of Denmark 
Helmholtz Zentrum München 
University Medical Center Utrecht 
University of Pennsylvania 
Massachusetts Institute of Technology 
National Heart,Lung,and Blood Institute (NHLBI) 
University of Copenhagen 
Erasmus University Rotterdam 
Vanderbilt University 
National Institute on Aging 
Publication Type: Peer Reviewed
Appears in Collections:Άρθρα/Articles

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