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Cited by 49Cardiac electrophysiology and arrhythmiasGenetic Associations and EpidemiologyCardiovascular Effects of Exercise

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

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Young, William J., Lahrouchi, Najim, Isaacs, Aaron, Duong, ThuyVy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A., Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E., Weiss, Stefan, Baldassari, Antoine R., Bartz, Traci M., Cook, James P., Evans, Daniel S., Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L., Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A., Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R., Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C., Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J., Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T., Felix, Stephan B., Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Claus, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R., Huang, Paul L., Huikuri, Heikki V., Hutri-Kähönen, Nina, Ikram, M. Arfan, Jackson, Rebecca D., Junttila, Juhani, Kavousi, Maryam, Kors, Jan A., Leal, Thiago P., Lemaitre, Rozenn N., Lin, Henry J., Lind, Lars, Linneberg, Allan, Liu, Simin, MacFarlane, Peter W., Mangino, Massimo, Meitinger, Thomas, Mezzavilla, Massimo, Mishra, Pashupati P., Mitchell, Rebecca N., Mononen, Nina, Montasser, May E., Morrison, Alanna C., Nauck, Matthias, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K., Pelliccione, Giulia, Pittman, Alan, Porteous, David J., Pramstaller, Peter P., Preuss, Michael H., Raitakari, Olli T., Reiner, Alexander P., Ribeiro, Antonio Luiz P., Rice, Kenneth M., Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M. Benjamin, Sinagra, Gianfranco, Sinner, Moritz F., Soliman, Elsayed Z., Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D., Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A., Wilson, James G., Avery, Christy L., Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcus, Gharib, Sina A., Girotto, Giorgia, Grarup, Niels, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J. Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K., Kooperberg, Charles, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J. F., Lubitz, Steven A., Mook-Kanamori, Dennis O., Morris, Andrew P., O’Connell, Jeffrey R., Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M., Rotter, Jerome I., Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M., Verweij, Niek, Wilson, James F., Arking, Dan E., Ramirez, Julia, Lambiase, Pier D., Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B.·2022·Nature Communications
DOI 10.1038/s41467-022-32821-zPMC PMC9436946

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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.

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Authors
Young, W. J., Lahrouchi, N., Isaacs, A., Duong, T., Foco, L., Ahmed, F., Brody, J. A., Salman, R., Noordam, R., Benjamins, J.-W., Haessler, J., Lyytikäinen, L.-P., Repetto, L., Concas, M. P., van den Berg, M. E., Weiss, S., Baldassari, A. R., Bartz, T. M., Cook, J. P., Evans, D. S., Freudling, R., Hines, O., Isaksen, J. L., Lin, H., Mei, H., Moscati, A., Müller-Nurasyid, M., Nursyifa, C., Qian, Y., Richmond, A., Roselli, C., Ryan, K. A., Tarazona-Santos, E., Thériault, S., van Duijvenboden, S., Warren, H. R., Yao, J., Raza, D., Aeschbacher, S., Ahlberg, G., Alonso, A., Andreasen, L., Bis, J. C., Boerwinkle, E., Campbell, A., Catamo, E., Cocca, M., Cutler, M. J., Darbar, D., De Grandi, A., De Luca, A., Ding, J., Ellervik, C., Ellinor, P. T., Felix, S. B., Froguel, P., Fuchsberger, C., Gögele, M., Graff, C., Graff, M., Guo, X., Hansen, T., Heckbert, S. R., Huang, P. L., Huikuri, H. V., Hutri-Kähönen, N., Ikram, M. A., Jackson, R. D., Junttila, J., Kavousi, M., Kors, J. A., Leal, T. P., Lemaitre, R. N., Lin, H. J., Lind, L., Linneberg, A., Liu, S., MacFarlane, P. W., Mangino, M., Meitinger, T., Mezzavilla, M., Mishra, P. P., Mitchell, R. N., Mononen, N., Montasser, M. E., Morrison, A. C., Nauck, M., Nauffal, V., Navarro, P., Nikus, K., Pare, G., Patton, K. K., Pelliccione, G., Pittman, A., Porteous, D. J., Pramstaller, P. P., Preuss, M. H., Raitakari, O. T., Reiner, A. P., Ribeiro, A. L. P., Rice, K. M., Risch, L., Schlessinger, D., Schotten, U., Schurmann, C., Shen, X., Shoemaker, M. B., Sinagra, G., Sinner, M. F., Soliman, E. Z., Stoll, M., Strauch, K., Tarasov, K., Taylor, K. D., Tinker, A., Trompet, S., Uitterlinden, A., Völker, U., Völzke, H., Waldenberger, M., Weng, L.-C., Whitsel, E. A., Wilson, J. G., Avery, C. L., Conen, D., Correa, A., Cucca, F., Dörr, M., Gharib, S. A., Girotto, G., Grarup, N., Hayward, C., Jamshidi, Y., Järvelin, M.-R., Jukema, J. W., Kääb, S., Kähönen, M., Kanters, J. K., Kooperberg, C., Lehtimäki, T., Lima-Costa, M. F., Liu, Y., Loos, R. J. F., Lubitz, S. A., Mook-Kanamori, D. O., Morris, A. P., O’Connell, J. R., Olesen, M. S., Orini, M., Padmanabhan, S., Pattaro, C., Peters, A., Psaty, B. M., Rotter, J. I., Stricker, B., van der Harst, P., van Duijn, C. M., Verweij, N., Wilson, J. F., Arking, D. E., Ramirez, J., Lambiase, P. D., Sotoodehnia, N., Mifsud, B., Newton-Cheh, C., & Munroe, P. B.
Affiliations
  • St Bartholomew's Hospital (GB)
  • Broad Institute (US)
  • Maastricht University (NL)
  • Johns Hopkins University (US)
  • Eurac Research (IT)
  • Queen Mary University of London (GB)
  • University of Washington (US)
  • Leiden University Medical Center (NL)
  • University Medical Center Groningen (NL)
  • Fred Hutch Cancer Center (US)
  • Tampere University (FI)
  • University of Edinburgh (GB)
  • IRCCS Materno Infantile Burlo Garofolo (IT)
  • Erasmus MC (NL)
  • Universitätsmedizin Greifswald (DE)
  • University of North Carolina at Chapel Hill (US)
  • University of Liverpool (GB)
  • California Pacific Medical Center (US)
  • Helmholtz Munich (DE)
  • St George's, University of London (GB)
  • University of Copenhagen (DK)
  • Boston University (US)
  • University of Mississippi Medical Center (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • National Institute on Aging (US)
  • Western General Hospital (GB)
  • University of Maryland, Baltimore (US)
  • Population Health Research Institute (CA)
  • The Lundquist Institute (US)
  • Brighton and Sussex Medical School (GB)
  • University of Basel (CH)
  • Baylor College of Medicine (US)
  • Intermountain Healthcare (US)
  • University of Illinois Chicago (US)
  • Centre National de la Recherche Scientifique (FR)
  • Aalborg University (DK)
  • University of California, Los Angeles (US)
  • Massachusetts General Hospital (US)
  • Oulu University Hospital (FI)
  • The Ohio State University Wexner Medical Center (US)
  • Universidade Federal de Minas Gerais (BR)
  • Uppsala University (SE)
  • Brown University (US)
  • University of Glasgow (GB)
  • King's College London (GB)
  • The University of Texas Health Science Center at Houston (US)
  • Institute of Genetics and Cancer (GB)
  • University of Turku (FI)
  • University of Bern (CH)
  • Hasso Plattner Institute (DE)
  • Fudan University (CN)
  • Vanderbilt University Medical Center (US)
  • University of Trieste (IT)
  • German Centre for Cardiovascular Research (DE)
  • Wake Forest University Health Sciences (US)
  • University of Münster (DE)
  • Johannes Gutenberg University Mainz (DE)
  • Beth Israel Deaconess Medical Center (US)
  • Institute of Genetic and Biomedical Research (IT)
  • Duke University (US)
  • Centre for Human Genetics (GB)
Corresponding author
Munroe, Patricia B.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-09-01
Volume
13
Issue
1
Pages
5144-5144
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-32821-z
PMC
PMC9436946
OpenAlex
W4294068885
Cited by
49
References
118
Citations by year
2026: 7 · 2025: 18 · 2024: 14 · 2023: 10
FWCI
7.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, cc-by)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • VBN Forskningsportal (Aalborg Universitet) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • UTUPub (University of Turku) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion)
  • publish.UP (University of Potsdam) (submittedVersion, cc-by)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion, cc-by)
  • VBN Forskningsportal (Aalborg Universitet) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
  • Open Research (University of Surrey) (submittedVersion, other-oa)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • UTUPub (University of Turku) (submittedVersion)
  • Zaguan (University of Zaragoza Repository) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, cc-by)
Funders
Individual author funding is supplied in the acknowledgements section. Study funding is supplied in detail, in Supplementary Note 6 - Study funding.
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
Keywords
QT interval, JT interval, QRS duration, ventricular repolarization, ventricular depolarization, genetic loci, rare variants, Mendelian disease genes, insulin receptor signaling, myocardial energy metabolism, extracellular matrix, atrial fibrillation, cardiac conduction disorders, sudden cardiac death, polygenic risk score, druggable genes, cardiac arrhythmias
MeSH terms
Arrhythmias, Cardiac, Electrocardiography, Genetic Testing, Humans, Male, Death, Sudden, Cardiac

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