Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro Grandi, Antonio Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim Harst, Cornelia M. Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh () and Patricia B. Munroe ()
Additional contact information
William J. Young: Queen Mary University of London
Najim Lahrouchi: Amsterdam Cardiovascular Sciences
Aaron Isaacs: Cardiovascular Research Institute Maastricht CARIM, Maastricht University
ThuyVy Duong: Johns Hopkins University School of Medicine
Luisa Foco: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Farah Ahmed: Queen Mary University of London
Jennifer A. Brody: University of Washington
Reem Salman: Queen Mary University of London
Raymond Noordam: Leiden University Medical Center
Jan-Walter Benjamins: Department of Cardiology
Jeffrey Haessler: Fred Hutchinson Cancer Center
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Linda Repetto: Usher Institute, University of Edinburgh
Maria Pina Concas: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Marten E. Berg: Erasmus MC – University Medical Center
Stefan Weiss: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Antoine R. Baldassari: University of North Carolina at Chapel Hill
Traci M. Bartz: University of Washington
James P. Cook: University of Liverpool
Daniel S. Evans: Research Institute
Rebecca Freudling: University Hospital, LMU Munich
Oliver Hines: St George’s University of London
Jonas L. Isaksen: University of Copenhagen
Honghuang Lin: National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Hao Mei: University of Mississippi Medical Center
Arden Moscati: Icahn School of Medicine at Mount Sinai
Martina Müller-Nurasyid: Helmholtz Zentrum München - German Research Center for Environmental Health
Casia Nursyifa: University of Copenhagen
Yong Qian: National Institute of Health
Anne Richmond: University of Edinburgh, Western General Hospital
Carolina Roselli: Department of Cardiology
Kathleen A. Ryan: University of Maryland School of Medicine
Eduardo Tarazona-Santos: Universidade Federal de Minas Gerais
Sébastien Thériault: McMaster University
Stefan Duijvenboden: Queen Mary University of London
Helen R. Warren: Queen Mary University of London
Jie Yao: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Dania Raza: Queen Mary University of London
Stefanie Aeschbacher: University Hospital Basel, University of Basel
Gustav Ahlberg: Copenhagen University Hospital, Rigshospitalet
Alvaro Alonso: Emory University
Laura Andreasen: Copenhagen University Hospital, Rigshospitalet
Joshua C. Bis: University of Washington
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Archie Campbell: Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter
Eulalia Catamo: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Massimiliano Cocca: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Michael J. Cutler: Intermountain Medical Center
Dawood Darbar: University of Illinois at Chicago
Alessandro Grandi: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Antonio Luca: ASUGI, University of Trieste
Jun Ding: National Institute of Health
Christina Ellervik: Department of Data and Data Support, Region Zealand
Patrick T. Ellinor: Broad Institute
Stephan B. Felix: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Philippe Froguel: School of Public Health, Imperial College London
Christian Fuchsberger: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Martin Gögele: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Claus Graff: Aalborg University
Mariaelisa Graff: University of North Carolina at Chapel Hill
Xiuqing Guo: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Torben Hansen: University of Copenhagen
Susan R. Heckbert: University of Washington
Paul L. Huang: Massachusetts General Hospital
Heikki V. Huikuri: University of Oulu and University Hospital of Oulu
Nina Hutri-Kähönen: Tampere University Hospital
M. Arfan Ikram: Erasmus MC – University Medical Center
Rebecca D. Jackson: Ohio State Medical Center
Juhani Junttila: University of Oulu and University Hospital of Oulu
Maryam Kavousi: Erasmus MC – University Medical Center
Jan A. Kors: Erasmus University Medical Center
Thiago P. Leal: Universidade Federal de Minas Gerais
Rozenn N. Lemaitre: University of Washington
Henry J. Lin: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Lars Lind: Uppsala University
Allan Linneberg: Bispebjerg and Frederiksberg Hospital
Simin Liu: Medicine and Surgery, Brown University
Peter W. MacFarlane: Veterinary and Life Sciences, University of Glasgow
Massimo Mangino: King’s College London
Thomas Meitinger: Helmholtz Zentrum München - German Research Center for Environmental Health
Massimo Mezzavilla: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Pashupati P. Mishra: Fimlab Laboratories
Rebecca N. Mitchell: Johns Hopkins University School of Medicine
Nina Mononen: Fimlab Laboratories
May E. Montasser: University of Maryland School of Medicine
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Matthias Nauck: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Victor Nauffal: Broad Institute
Pau Navarro: Institute of Genetics and Cancer, University of Edinburgh
Kjell Nikus: Tampere University Hospital
Guillaume Pare: McMaster University
Kristen K. Patton: University of Washington
Giulia Pelliccione: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Alan Pittman: St George’s University of London
David J. Porteous: University of Edinburgh, Western General Hospital
Peter P. Pramstaller: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Michael H. Preuss: Icahn School of Medicine at Mount Sinai
Olli T. Raitakari: University of Turku and Turku University Hospital
Alexander P. Reiner: Department of Epidemiology/University of Washington
Antonio Luiz P. Ribeiro: Universidade Federal de Minas Gerais, Brazil
Kenneth M. Rice: University of Washington
Lorenz Risch: Labormedizinisches zentrum Dr. Risch
David Schlessinger: National Institute on Aging, National Institute of Health
Ulrich Schotten: Cardiovascular Research Institute Maastricht CARIM, Maastricht University
Claudia Schurmann: Icahn School of Medicine at Mount Sinai
Xia Shen: Usher Institute, University of Edinburgh
M. Benjamin Shoemaker: Arrhythmia Section, Vanderbilt University Medical Center
Gianfranco Sinagra: ASUGI, University of Trieste
Moritz F. Sinner: University Hospital, LMU Munich
Elsayed Z. Soliman: Wake Forest School of Medicine
Monika Stoll: Maastricht University
Konstantin Strauch: Helmholtz Zentrum München - German Research Center for Environmental Health
Kirill Tarasov: National Institute on Aging, National Institute of Health
Kent D. Taylor: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Andrew Tinker: Queen Mary University of London
Stella Trompet: Leiden University Medical Center
André Uitterlinden: Internal Medicine, Erasmus MC
Uwe Völker: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Henry Völzke: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Melanie Waldenberger: DZHK (German Centre for Cardiovascular Research, partner site: Munich Heart Alliance
Lu-Chen Weng: Broad Institute
Eric A. Whitsel: University of North Carolina at Chapel Hill
James G. Wilson: University of Mississippi Medical Center
Christy L. Avery: University of North Carolina at Chapel Hill
David Conen: McMaster University
Adolfo Correa: University of Mississippi Medical Center
Francesco Cucca: Italian National Research Council
Marcus Dörr: DZHK German Centre for Cardiovascular Research; partner site Greifswald
Sina A. Gharib: Critical Care and Sleep Medicine, University of Washington
Giorgia Girotto: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Niels Grarup: University of Copenhagen
Caroline Hayward: University of Edinburgh, Western General Hospital
Yalda Jamshidi: St George’s University of London
Marjo-Riitta Järvelin: Faculty of Medicine, University of Oulu
J. Wouter Jukema: Leiden University Medical Center
Stefan Kääb: University Hospital, LMU Munich
Mika Kähönen: Tampere University Hospital
Jørgen K. Kanters: University of Copenhagen
Charles Kooperberg: Fred Hutchinson Cancer Center
Terho Lehtimäki: Fimlab Laboratories
Maria Fernanda Lima-Costa: Instituto René Rachou, fundação Oswaldo Cruz
Yongmei Liu: Duke University
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Steven A. Lubitz: Broad Institute
Dennis O. Mook-Kanamori: Leiden University Medical Center
Andrew P. Morris: University of Liverpool
Jeffrey R. O’Connell: University of Maryland School of Medicine
Morten Salling Olesen: University of Copenhagen
Michele Orini: Barts Health NHS trust
Sandosh Padmanabhan: University of Glasgow
Cristian Pattaro: Eurac Research, Institute for Biomedicine affiliated with the University of Lübeck
Annette Peters: Helmholtz Zentrum München - German Research Center for Environmental Health
Bruce M. Psaty: University of Washington
Jerome I. Rotter: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Bruno Stricker: Erasmus MC – University Medical Center
Pim Harst: Department of Cardiology
Cornelia M. Duijn: University of Oxford
Niek Verweij: Department of Cardiology
James F. Wilson: Usher Institute, University of Edinburgh
Dan E. Arking: Johns Hopkins University School of Medicine
Julia Ramirez: Queen Mary University of London
Pier D. Lambiase: Barts Health NHS trust
Nona Sotoodehnia: Department of Medicine, University of Washington
Borbala Mifsud: Queen Mary University of London
Christopher Newton-Cheh: Broad Institute of Harvard and MIT
Patricia B. Munroe: Queen Mary University of London

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Date: 2022
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DOI: 10.1038/s41467-022-32821-z

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