Article | Published:

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

Nature Genetics volume 46, pages 826836 (2014) | Download Citation

This article has been updated

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.

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Change history

  • 20 July 2014

    In the version of this article initially published online, the name of Fabiola del Greco M was misspelled in the author list. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

A full listing of acknowledgments is provided in the Supplementary Note.

Author information

Author notes

    • Dan E Arking
    • , Sara L Pulit
    • , Michael J Ackerman
    • , Arne Pfeufer
    • , Paul I W de Bakker
    •  & Christopher Newton-Cheh

    These authors contributed equally to this work.

Affiliations

  1. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Dan E Arking
    • , Georg Ehret
    •  & Aravinda Chakravarti
  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sara L Pulit
    • , Peter A Noseworthy
    • , J Gustav Smith
    •  & Christopher Newton-Cheh
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Sara L Pulit
    • , Elizabeth J Rossin
    • , Alicia Lundby
    • , Peter A Noseworthy
    • , Soumya Raychaudhuri
    • , Hailiang Huang
    • , J Gustav Smith
    • , Mark J Daly
    • , Kasper Lage
    •  & Christopher Newton-Cheh
  4. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Sara L Pulit
    •  & Paul I W de Bakker
  5. Department of Molecular Medicine, Section of Cardiology, University of Pavia, Pavia, Italy.

    • Lia Crotti
    • , Alice Ghidoni
    •  & Roberto Insolia
  6. Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricerca e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy.

    • Lia Crotti
    • , Alice Ghidoni
    • , Roberto Insolia
    •  & Peter J Schwartz
  7. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Lia Crotti
  8. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Pim van der Harst
    • , Rudolf A de Boer
    • , Pieter A van der Vleuten
    • , Irene Mateo Leach
    • , Maarten P van den Berg
    •  & Dirk J van Veldhuisen
  9. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Pim van der Harst
    • , Lude Franke
    •  & Pieter A van der Vleuten
  10. Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

    • Patricia B Munroe
    • , Stephen J Newhouse
    •  & Mark J Caulfield
  11. Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

    • Patricia B Munroe
  12. Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.

    • Tamara T Koopmann
    • , Abdennasser Bardai
    • , Arthur A M Wilde
    •  & Connie R Bezzina
  13. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nona Sotoodehnia
    • , Joshua C Bis
    • , Susan R Heckbert
    • , Bruce M Psaty
    •  & David S Siscovick
  14. Cardiology Division, University of Washington, Seattle, Washington, USA.

    • Nona Sotoodehnia
  15. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Elizabeth J Rossin
    • , Hailiang Huang
    • , Mark J Daly
    •  & Kasper Lage
  16. Harvard Medical School, Boston, Massachusetts, USA.

    • Elizabeth J Rossin
    • , Hailiang Huang
    •  & Christopher Newton-Cheh
  17. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Michael Morley
    • , Jeffrey Brandimarto
    • , Kenneth Margulies
    • , Christine E Moravec
    •  & Thomas P Cappola
  18. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Xinchen Wang
    •  & Manolis Kellis
  19. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Xinchen Wang
    •  & Manolis Kellis
  20. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Xinchen Wang
    •  & Laurie A Boyer
  21. National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA.

    • Andrew D Johnson
    • , Martin G Larson
    • , Christopher J O'Donnell
    •  & Xiaoyan Yin
  22. Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Alicia Lundby
    • , Jesper V Olsen
    •  & Kasper Lage
  23. The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.

    • Alicia Lundby
  24. deCODE genetics, Reykjavik, Iceland.

    • Daníel F Gudbjartsson
    • , Hilma Hólm
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  25. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Peter A Noseworthy
    • , J Gustav Smith
    •  & Christopher Newton-Cheh
  26. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Mark Eijgelsheim
    • , Bouwe P Krijthe
    • , Oscar H Franco
    • , Albert Hofman
    • , André G Uitterlinden
    • , Jacqueline C M Witteman
    • , Ben A Oostra
    • , Cornelia M van Duijn
    •  & Bruno H Stricker
  27. Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Yuki Bradford
    •  & Rebecca L Zuvich
  28. Laboratory of Cardiovascular Sciences, Human Cardiovascular Studies Unit, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.

    • Kirill V Tarasov
    • , James B Strait
    •  & Edward G Lakatta
  29. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

    • Marcus Dörr
    •  & Stephan B Felix
  30. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

    • Marcus Dörr
    • , Uwe Völker
    •  & Stephan B Felix
  31. Department of Medicine I, University Hospital Munich, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
    • , Moritz F Sinner
    • , Britt Maria Beckmann
    • , Eimo Martens
    •  & Stefan Kääb
  32. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  33. Institute of Genetic Epidemiology, Helmholtz Zentrum Munich–German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Müller-Nurasyid
    •  & Christian Gieger
  34. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Munich, Germany.

    • Martina Müller-Nurasyid
  35. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

    • Martina Müller-Nurasyid
    • , Thomas Meitinger
    • , Annette Peters
    •  & Stefan Kääb
  36. Research Programs Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland.

    • Annukka M Lahtinen
    •  & Annukka Marjamaa
  37. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.

    • Annukka M Lahtinen
    •  & Annukka Marjamaa
  38. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Ilja M Nolte
    •  & Harold Snieder
  39. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith
    • , Valur Emilsson
    •  & Vilmundur Gudnason
  40. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert Vernon Smith
    • , Vilmundur Gudnason
    •  & Kari Stefansson
  41. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Aaron Isaacs
  42. California Pacific Medical Center Research Institute, San Francisco, California, USA.

    • Daniel S Evans
    •  & Steven R Cummings
  43. Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Wendy S Post
  44. Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Wendy S Post
    •  & W H Linda Kao
  45. Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Daryl Waggott
  46. Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    • , Nina Mononen
    •  & Terho J Lehtimäki
  47. Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany).

    • Andrew A Hicks
    • , Fabiola del Greco M
    • , Peter P Pramstaller
    •  & Arne Pfeufer
  48. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

    • Lewin Eisele
    •  & Karl-Heinz Jöckel
  49. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • David Ellinghaus
    •  & Andre Franke
  50. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • Caroline Hayward
    • , Pau Navarro
    •  & Alan F Wright
  51. Institute for Maternal and Child Health, “Burlo Garofolo” Trieste, Trieste, Italy.

    • Sheila Ulivi
    • , Adamo P D'Adamo
    •  & Paolo Gasparini
  52. Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka
    • , James B Strait
    •  & Luigi Ferrucci
  53. Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.

    • David J Tester
    •  & Michael J Ackerman
  54. Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

    • David J Tester
    • , John R Giudicessi
    • , Argelia Medeiros-Domingo
    •  & Michael J Ackerman
  55. Institut du Thorax, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France.

    • Stéphanie Chatel
    • , Florence Kyndt
    • , Vincent Probst
    •  & Jean-Jacques Schott
  56. Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, Université de Nantes, Nantes, France.

    • Stéphanie Chatel
    • , Julien Barc
    • , Florence Kyndt
    • , Vincent Probst
    •  & Jean-Jacques Schott
  57. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Stefan Gustafsson
  58. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Gustafsson
    • , Marcel den Hoed
    • , Johan Ärnlöv
    • , Ann-Christine Syvänen
    •  & Erik Ingelsson
  59. Institute of Cardiovascular Science, University College London, London, UK.

    • Meena Kumari
    • , Mika Kivimaki
    •  & Aroon D Hingorani
  60. Department of Primary Care and Population Health, University College London, Royal Free Campus, London, UK.

    • Richard W Morris
  61. Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

    • Åsa T Naluai
  62. Biobanking and Molecular Resource Infrastructure of Sweden (BBMRI), Gothenburg, Sweden.

    • Åsa T Naluai
  63. BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • Sandosh Padmanabhan
    • , Wai K Lee
    •  & Anna F Dominiczak
  64. Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle, Germany.

    • Alexander Kluttig
    • , Karin H Greiser
    •  & Johannes Haerting
  65. Second Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria.

    • Bernhard Strohmer
  66. Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health, Cyprus University of Technology, Limassol, Cyprus.

    • Andrie G Panayiotou
  67. Cyprus Cardiovascular and Educational Research Trust, Nicosia, Cyprus.

    • Andrie G Panayiotou
    •  & Andrew N Nicolaides
  68. Grupo de Medicina Xenómica, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.

    • Maria Torres
    • , Angel Carracedo
    •  & Maria Brion
  69. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

    • Michael Knoflach
    • , Johann Willeit
    •  & Stefan Kiechl
  70. Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

    • Jaroslav A Hubacek
    •  & Vera Adamkova
  71. Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Kamil Slowikowski
    •  & Soumya Raychaudhuri
  72. Harvard Bioinformatics and Integrative Genomics, Boston, Massachusetts, USA.

    • Kamil Slowikowski
  73. Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  74. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  75. Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

    • Soumya Raychaudhuri
  76. Computational and Systems Biology Program, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri, USA.

    • Runjun D Kumar
  77. Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Runjun D Kumar
  78. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  79. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Alan R Shuldiner
    • , Jeffrey R O'Connell
    •  & Afshin Parsa
  80. Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.

    • Alan R Shuldiner
    • , Jeffrey R O'Connell
    •  & Afshin Parsa
  81. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  82. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alvaro Alonso
  83. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

    • Joel S Bader
  84. Electrocardiology, University of Glasgow Institute of Cardiovascular and Medical Sciences, Royal Infirmary, Glasgow, UK.

    • Peter W Macfarlane
  85. Clinical Pharmacology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Morris Brown
  86. Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  87. Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.

    • Florian Kronenberg
    •  & Claudia Lamina
  88. Department of Cardiology, Lund University, Lund, Sweden.

    • J Gustav Smith
  89. Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.

    • Karin H Greiser
  90. Department of Pharmacology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.

    • Henriette Meyer zu Schwabedissen
  91. Department of Medicine III, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.

    • Karl Werdan
  92. Medical Genetics Unit, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

    • Massimo Carella
    •  & Leopoldo Zelante
  93. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Susan R Heckbert
    • , Bruce M Psaty
    •  & David S Siscovick
  94. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  95. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Bruce M Psaty
  96. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & David S Siscovick
  97. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles (UCLA) Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  98. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.

    • Ivana Kolcic
    •  & Ozren Polašek
  99. Vascular Screening and Diagnostic Centre, London, UK.

    • Maura Griffin
    •  & Andrew N Nicolaides
  100. Department of Medicine, Division of Cardiology, Landspitali University Hospital, Reykjavik, Iceland.

    • David O Arnar
  101. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Joshua C Denny
  102. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Joshua C Denny
    •  & Dan M Roden
  103. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.

    • Dan M Roden
  104. Office of Personalized Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • Dan M Roden
  105. Sanofi Research and Development, Paris, France.

    • Andrew S Plump
  106. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Martin G Larson
    •  & Xiaoyan Yin
  107. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Martin G Larson
  108. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  109. Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.

    • Marco Bobbo
    • , Annamaria Iorio
    •  & Gianfranco Sinagra
  110. Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

    • Adamo P D'Adamo
    •  & Paolo Gasparini
  111. Fundación Publica Galega de Medicina Xenómica, Servicio Galego de Saude, Santiago de Compostela, Spain.

    • Angel Carracedo
  112. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Angel Carracedo
  113. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Michael A Nalls
  114. Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Antti Jula
    •  & Veikko Salomaa
  115. Department of Medicine, University of Helsinki, Helsinki, Finland.

    • Kimmo K Kontula
  116. Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

    • Lasse Oikarinen
    •  & Kimmo Porthan
  117. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Markus Perola
  118. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Markus Perola
  119. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Markus Perola
  120. Department of Cardiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

    • Raimund Erbel
    •  & Hagen Kälsch
  121. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Per Hoffmann
    • , Markus M Nöthen
    •  & Thomas W Mühleisen
  122. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Per Hoffmann
    • , Markus M Nöthen
    •  & Thomas W Mühleisen
  123. Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.

    • Per Hoffmann
  124. Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Per Hoffmann
  125. MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Marcel den Hoed
    •  & Ruth J F Loos
  126. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  127. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  128. Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

    • Dag S Thelle
  129. Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Dag S Thelle
    •  & Fredrik Nyberg
  130. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
    •  & Arne Pfeufer
  131. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Meitinger
    •  & Melanie Waldenberger
  132. Institute for Biological and Medical Imaging, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Siegfried Perz
  133. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Annette Peters
  134. Christine Kühne–Center for Allergy and Education, Munich, Germany.

    • Hanna Prucha
  135. Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.

    • Hanna Prucha
  136. Department of Medicine, Hospital of Friedberg, Friedberg, Germany.

    • Eimo Martens
  137. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

    • Nynke Hofman
  138. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.

    • Arthur A M Wilde
  139. Cardiovascular and Cell Sciences Institute, St George's University of London, London, UK.

    • Elijah R Behr
  140. Biomedical Sciences, St George's University of London, London, UK.

    • Chrysoula Dalageorgou
  141. The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Robert M Hamilton
  142. Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Robert M Hamilton
  143. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Stephen W Scherer
  144. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Christian Fuchsberger
    •  & Gonçalo R Abecasis
  145. General Practice and Primary Care, University of Glasgow, Glasgow, UK.

    • Graham C M Watt
  146. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Harry Campbell
    • , Sarah H Wild
    • , James F Wilson
    •  & Igor Rudan
  147. Biobank PopGen, Institute of Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.

    • Nour E El Mokhtari
  148. Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Norbert Frey
  149. Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of The Netherlands–Netherlands Heart Institute, Utrecht, The Netherlands.

    • Folkert W Asselbergs
  150. Department of Cardiology, Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands.

    • Folkert W Asselbergs
  151. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.

    • Folkert W Asselbergs
  152. Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Gerjan Navis
  153. Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.

    • Bouwe P Krijthe
    • , Oscar H Franco
    • , Albert Hofman
    • , André G Uitterlinden
    • , Jacqueline C M Witteman
    •  & Bruno H Stricker
  154. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Jan A Kors
    •  & Bruno H Stricker
  155. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • André G Uitterlinden
    •  & Bruno H Stricker
  156. First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria.

    • Lyudmyla Kedenko
    •  & Bernhard Paulweber
  157. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.

    • Antonella Mulas
    • , Marco Orrú
    • , Manuela Uda
    •  & Serena Sanna
  158. Laboratory of Genetics, Intramural Research Program, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.

    • David Schlessinger
  159. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Marcello R P Markus
  160. Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Uwe Völker
  161. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Timothy D Spector
  162. School of Health and Social Sciences, Dalarna University, Falun, Sweden.

    • Johan Ärnlöv
  163. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Lars Lind
    •  & Johan Sundström
  164. Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Mika Kähönen
  165. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  166. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  167. Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland.

    • Jorma S Viikari
  168. Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Complexo Hospitalario Universitario de Santiago de Compostela, Servicio Galego de Saude, Santiago de Compostela, Spain.

    • Maria Brion
  169. Global Epidemiology, AstraZeneca Research and Development, Mölndal, Sweden.

    • Fredrik Nyberg
  170. Division of Population Health Sciences and Education, St George's University of London, London, UK.

    • Peter H Whincup
  171. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Erik Ingelsson
  172. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Juelich, Juelich, Germany.

    • Thomas W Mühleisen
  173. Department of Neurology, University of Lübeck, Lübeck, Germany.

    • Peter P Pramstaller
  174. Department of Neurology, General Central Hospital, Bolzano, Italy.

    • Peter P Pramstaller
  175. Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.

    • Andrew D Paterson
  176. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  177. Human Genetics Research Centre, St George's University of London, London, UK.

    • Yalda Jamshidi
  178. Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.

    • Marylyn D Ritchie
  179. Inspectorate of Health Care, The Hague, The Netherlands.

    • Bruno H Stricker
  180. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.

    • Kasper Lage
  181. Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Kasper Lage
  182. Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.

    • Michael J Ackerman
  183. Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum, Munich, Germany.

    • Arne Pfeufer
  184. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Paul I W de Bakker

Consortia

  1. CARe Consortium

    Full list of members and affiliations appear in the Supplementary Note.

  2. COGENT Consortium

    Full list of members and affiliations appear in the Supplementary Note.

  3. DCCT/EDIC

    Full list of members and affiliations appear in the Supplementary Note.

  4. eMERGE Consortium

    Full list of members and affiliations appear in the Supplementary Note.

  5. HRGEN Consortium

    Full list of members and affiliations appear in the Supplementary Note.

Authors

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Contributions

Author contributions are indicated by cohort and group. All coauthors revised and approved the manuscript.

Writing group. C.N.-C. takes overall responsibility for the QT-IGC study. The study design was developed by M.J.A., D.E.A., A. Chakravarti, L.C., P.I.W.d.B., T.T.K., P.B.M., C.N.-C., A. Pfeufer, S.L.P., P.J.S. and N.S. in consultation with the respective study groups. The manuscript was written by C.N.-C. The manuscript was critically revised in detail by members of the writing team before circulation to all coauthors.

GWAS cohorts. AGES: Phenotyping: V.G. Data analysis: A.V.S. Oversight: T.B.H., L.J.L., V.G. Amish studies: Clinical data collection, genotyping and oversight: A.R.S. EKG data collection: W.S.P. Analysis: A. Parsa, J.R.O. Interpretation: A. Parsa, W.S.P. ARIC: Study design: A.A., D.E.A., A. Chakravarti, W.H.L.K. Analyses: D.E.A., J.S.B., A. Chakravarti, G.E., H. Huang. Steering: D.E.A., A. Chakravarti. Writing: D.E.A., A. Chakravarti. BLSA: Analysis: T.T. Phenotype collection: J.B.S. Overall project supervision: L. Ferrucci. BRIGHT: Phenotyping: M. Brown, M.J.C., P.W.M., P.B.M., N.J.S. Genotyping: P.B.M., S.J.N. Analysis: S.J.N. Overall study supervision: M. Brown, M.J.C., P.B.M., N.J.S. Carlantino: Sample and/or data collection: M.C., L.Z. Overall study supervision: P.G. Data collection and/or statistical analysis: S.U. CHS: Study design: J.C.B., S.R.H., B.M.P., N.S. Data collection: S.R.H., B.M.P., D.S.S. Genotyping: J.I.R. Analysis, interpretation: J.C.B., N.S. Supervision of analyses: B.M.P. Funding for GWAS: B.M.P. Croatia-Korcula and Croatia-Split: GWAS analysis: C.H. Data collection, phenotype measurement, data entry and field work supervision: I.K., O.P. Study design and funding: I.R., A.F.W. DCCT/EDIC: Analyses: D.W. Supervision of analyses: A.D.P. deCODE: Data collection: D.O.A., H. Hólm. Study design: K. Stefansson, U.T., H. Hólm, D.F.G., D.O.A. Data alignment, imputation and statistical analysis: D.F.G. Additional analysis and interpretation of results: K. Stefansson, U.T., H. Hólm, D.F.G., D.O.A. eMERGE: Data curation and GWAS analysis: R.L.Z., Y.B. Supervision of quality control and analysis of data set: M.D.R. Study conception and analysis framework: D.M.R. Algorithm for case ascertainment: J.C.D. ERF: Analysis: A. Isaacs. Data acquisition: C.M.v.D., A. Isaacs, B.A.O., J.A.K., A.G.U. Overall study principal investigators: C.M.v.D., B.A.O. FHS: Analysis plan development: C.N.-C., C.J.O., P.A.N., M.G.L. GWAS analysis: X.Y., M.G.L. Secured funding: C.N.-C., C.J.O. FVG: Data collection: M. Bobbo. Primary analysis: A. Iorio. Statistical analysis: A.P.D.A. Overall study supervision: G.S. Health2000: Data analysis, replication genotyping and quality control: A.M.L. Primary data analysis: A. Marjamaa. Phenotyping, including ECGs: A.J. Electrocardiographic measurements: K.P. GWAS and replication genotyping: M.P. Design of ECG study, analysis and interpretation: L.O. Genetic data collection and analysis: K.K.K. Principal investigator and supervision: V.S. HealthABC: Data collection and supervision: S.R.C., Y.L. Data analysis: D.S.E., M.A.N. HNR: Data collection: H.K. Data generation: H.K., T.W.M. Genetic data generation: M.M.N., P.H., T.W.M. Data analysis: L.E., P.H., T.W.M., M.M.N. Overall study design and principal investigators: R.E., K.-H.J. KORA-F3/S4: Overall QT project supervision: A. Pfeufer. Genotyping oversight: T.M. ECG collection, measurement and interpretation: M.F.S., S. Perz, B.M.B., E.M. Primary genetic analysis: C.G., M.M.-N. Interpretation of results: C.G., A. Pfeufer, H.P., S. Kääb, T.M., M.W. Overall study principal investigator: A. Peters. LifeLines: Phenotyping: R.A.d.B., P.A.v.d.V. Genotyping: L. Franke. Analyses: I.M.N. and L. Franke. MICROS: Sample recruitment and overall study principal investigator: P.P.P. Study supervision, genotyping and data coordination: A.A.H. Data analysis: F.D.G.M., C.F. ORCADES: Phenotype collection: S.H.W. Genotype generation: H.C., J.F.W. GWAS analysis: P.N. Raised funding: J.F.W. Overall study supervision: J.F.W. PopGen: Recruitment and phenotyping: N.E.E.M., N.F. Genotyping and data preparation: A.F. Data preparation and analysis: D.E. PREVEND: Phenotyping: M.P.v.d.B., D.J.v.V., G.N. Genotyping and data analysis: F.W.A., I.M.L., P.v.d.H. Obtained funding: G.N., D.J.v.V., F.W.A., P.v.d.H. Rotterdam Study I and II: Study concept and design: M.E., B.H.S. Data acquisition: M.E., O.H.F., B.P.K., J.A.K., A.H., J.C.M.W., B.H.S., A.G.U. Statistical analysis: M.E. Interpretation: M.E., B.H.S. Obtained funding: A.H., J.C.M.W., A.G.U., B.H.S. Study supervision: B.H.S. SardiNIA: Phenotyping: M.O. Genotyping and data analysis: G.R.A., E.G.L., A. Mulas, M.O., S.S., D.S., K.V.T., M.U. Overall study supervision and principal investigators: D.S., M.U. SHIP: Data acquisition: M.D., M.R.P.M., U.V., S.B.F. Statistical analysis: U.V., M.D., M.R.P.M. Interpretation: U.V., M.D., S.B.F. Obtained funding: S.B.F., U.V. TwinsUK: Study concept and design: H.S., Y.J. Data acquisition: T.D.S. Statistical analysis and interpretation: I.M.N., H.S., Y.J. Obtained funding: Y.J., T.D.S. Young Finns Study: Data collection: T.J.L., O.T.R., M. Kähönen, J.S.V. Genotyping: T.J.L., N.M. Genotyping: T.J.L. Phenotype preparation: O.T.R., M. Kähönen, J.S.V. Analysis: T.J.L., O.T.R., M. Kähönen, J.S.V., L.-P.L. Obtained funding: T.J.L., O.T.R., M. Kähönen, J.S.V.

Directly genotyped SNP replication cohorts. (Author contributions for cohorts that contributed to both GWAS and replication genotyping are shown under the GWAS entry above.) BRHS: Analysis: R.W.M. Custodian of genetic resource: R.W.M., P.H.W. Data collection for genetic resource: P.H.W. Development of genetic resource: A.D.H. Overall study supervision and principal investigators: P.H.W., R.W.M. ECG analyses: P.W.M. Bruneck: Data analysis, interpretation and writing: S. Kiechl. DNA preparation: F. Kronenberg, C.L. ECG measurement and database: M. Knoflach. Supervision, funding, administration and principal investigator: J.W. Carla: Study concept and design: K.H.G., K.W. Genotyping: H.M.z.S. Supervision: K.W. Study design and analysis: A.K. Study concept, supervision and principal investigator: J.H. Cyprus: Study concept, funding, supervision and analysis: A.N.N. Data acquisition, analysis and interpretation: M.G. Genetic, biochemical data acquisition and statistical analysis: A.G.P. Czech Post-MONICA: Data collection and submission: J.A.H., V.A. Galicia: Cohort collection: M. Brion. Study design: M. Brion. Genotyping platform management: A. Carracedo. Genotyping: M.T. Analysis: M.T. Interpretation: M. Brion, A. Carracedo. Financial support: A. Carracedo. Intergene: Genotyping, data analysis and epidemiology expertise: F.N. Genotyping and genetic expertise: Å.T.N. Study design, data collection and disease area knowledge: D.S.T. MIDSPAN Family Study: Data acquisition, statistical analysis and interpretation: S. Padmanabhan. Genotyping: W.K.L. Overall study supervision, data collection and funding: A.F.D., G.C.M.W. PIVUS: Genotyping: A.-C.S. Phenotyping: L.L., J.Ä., J.S. Data analysis: S.G. Overall supervision and principal investigator: E.I. SAPHIR: DNA preparation: F. Kronenberg, C.L. Data collection: L.K., B.P., B.S. Data analysis: L.K., F. Kronenberg, C.L., B.P., B.S. Study design and principal investigator: B.P. ULSAM: Genotyping: A.-C.S. Phenotyping: L.L., J.Ä., J.S. Data analysis: S.G. Overall supervision and principal investigator: E.I. Whitehall II: Data collection and submission: M. Kumari. Overall supervision: M. Kivimaki. Funding: A.D.H.

Meta-analysis of GWAS and replication. D.E.A. and S.L.P. independently performed quality control and meta-analysis of GWAS and replication association results. Polygenic analysis: R.D.K. P.I.W.d.B., A. Pfeufer. and C.N.-C. supervised the analyses.

Non-QT trait lookups. CARe-COGENT: Meta-analysis and lookup: J.G.S. HRGEN: Meta-analysis and lookup: M.d.H. Overall study supervision: R.J.F.L. QRS GWAS: Study supervision: N.S. Meta-analysis: D.E.A., P.I.W.d.B. Results lookup: S.L.P.

Non-cardiac eQTL analyses. Data set acquisition: A.S.P., V.E. Analysis and interpretation: A.D.J. Cell type–specific enrichment tests: S.R., K. Slowikowski.

Left ventricle eQTL analyses. Overall supervision: T.P.C. Recruitment, sample collection: K.M., C.E.M. Sample processing and expression analysis: J. Brandimarto. Statistical analysis: M.M.

Left ventricle enhancer analyses. Analysis: X.W. Overall supervision: L.A.B., M. Kellis.

Mouse knockout. Enrichment tests: S.R., K. Slowikowski. Candidate gene list: P.v.d.H.

LQTS mutation screening. Amsterdam:SLC8A1 sequencing: T.T.K. Clinical data collection: A.B., N.H., A.A.M.W. Study supervision: C.R.B., A.A.M.W. London: Recruitment, phenotyping and strategy: E.R.B. Screening for mutations in LQT1, LQT2 and LQT3 and sample management: C.D. Mayo Clinic: LQTS cohort characteristic organization: D.J.T. TRPM7 mutation analysis and interpretation: D.J.T., A.M.-D., J.R.G. Patient collection, study design, data review and overall supervision: M.J.A. Munich: Study oversight: S. Kääb, A. Pfeufer. Patient collection: B.M.B., E.M. Genotyping: H.P. Nantes: Scientific management: J.-J.S. Clinical, genetic information collection: S.C. ATP2A2 sequencing: S.C. Screening for mutations in LQT1, LQT2 and LQT3 and clinical data collection: J. Barc. LQTS gene diagnosis management: F. Kyndt. Patient enrollment: V.P. Pavia: Patient collection, patient selection and molecular screening supervision: L.C., P.J.S. SRL mutation screening: A.G., R.I. Toronto: Identification of patients with LQTS free of LQT1, LQT2 and LQT3 mutations: R.M.H. Program codevelopment: S.W.S.

DAPPLE analysis. Concept, design and analysis: E.J.R. Supervision: K.L., M.J.D.

Immunoprecipitation experiments. Proteomic experiments and analysis: A.L. Overall study supervision: J.V.O.

Competing interests

H. Hólm is a former and D.O.A., D.F.G., K. Stefansson and U.T. are current full or part-time employees of deCODE Genetics/Amgen, Inc. A.S.P. was previously an employee of Merck Research Laboratory and is a current employee of Sanofi. F.N. is an employee of AstraZeneca. B.P. serves on the data and safety monitoring board for a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.S. serves on the advisory board of Itrim. M.J.A. is a consultant for Boston Scientific, Gilead Sciences, Medtronic and St. Jude Medical. M.J.A. and the Mayo Clinic receive royalties from Transgenomic with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests.

Corresponding author

Correspondence to Christopher Newton-Cheh.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–5, Supplementary Tables 1–3 and 5–18, and Supplementary Note

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    Supplementary Table 4

    Metabochip QT replication + fine-mapping of SNP content.

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https://doi.org/10.1038/ng.3014

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