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

William J. Young, Najim Lahrouchi, Aaron Isaacs, Thuy Vy 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. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. EvansRebecca 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 van 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 De Grandi, Antonio De 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 van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B. Munroe*

*Corresponding author for this work

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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.

Original languageEnglish
Article number5144
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
All study acknowledgements can be found in Supplementary Note , and study funding information in Supplementary Note . William J Young was supported by an MRC grant MR/R017468/1. Alvaro Alonso is supported by an NHLBI award K24HL148521. Antonio Luiz P Ribeiro is supported in part by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17 and RED-00081-16). Eduardo Tarazona-Santos, Maria Fernanda Lima-Costa and Thiago P Leal are supported by Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq). Eduardo Tarazona-Santos and Maria Fernanda Lima-Costa are also supported by the Brazilian Ministry of Health (DECIT/MS, EPIGEN-Brazil Project), Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos (FINEP) and Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG). Ruth Loos is supported by the National Institutes of Health (R01DK110113; R01DK107786; R01HL142302; R01DK124097). Michael J Cutler is supported by funding from the Dell Loy Hansen Heart Foundation. M.Benjamin Shoemaker is supported by grant NIHK23HL127704. Rozenn Lemaitre reports funding from grant: AHA 19SFRN34830063. Steven A Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Patrick T Ellinor was supported by grants from Bayer AG, the Foundation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), and the American Heart Association (18SFRN34110082). Lu-Chen Weng was supported by National Institutes of Health (NIH) grant 1R01HL139731 and American Heart Association (AHA) grant 18SFRN34110082. Victor Nauffal is funded by a T32 training grant from the National Institutes of Health (5T32HL007604-35). Nona Sotoodehnia is supported by grants AHA19SFRN348300063, R01HL141989, Medic One Foundation, Laughlin Family. Ulrich Schotten received funding from the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hypercoagulability, Electrical remodelling, and Vascular Destabilization in the Progression of AF), the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286). Sébastien Thériault is supported by a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Québec-Santé (FRQS). Jonas L Isaksen is supported by CACHET. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). Christy Avery and Antoine Baldassari were supported by NIH grants R01HL142825, and U01HG007416. Dawood Darbar was supported by NIH grants R01HL138737 and T32HL139439. Daniel S Evans is supported by NIH grant U24AG051129. Niels Grarup is supported by the Novo Nordisk Foundation (Grant number NNF18CC0034900). James G. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Hao Mei is also supported by the CHARGE infrastructure grant (HL105756). Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). May E Montasser receives funding from Regeneron Pharmaceutical unrelated to this work. James F Wilson and Pau Navarro acknowledge support from the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). Linda Repetto is funded by a University of Edinburgh studentship. Xia Shen was in receipt of a Starting Grant (2017-02543) from the Swedish Research Council (Vetenskaprådet). Lars Lind is funded by Uppsala University Hospital, Uppsala, Sweden. Niek Verweij was supported by NWO VENI (016.186.125). Jan-Walter Benjamins is funded by the Research Project CVON-AI (2018B017) financed by the PPP Allowance made available by Top Sector Life Sciences & Health to the Dutch Heart Foundation to stimulate public-private partnerships. J.Wouter Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Oliver Hines is supported by a Medical Research Council DTP Studentship. Massimo Mangino is supported by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Patricia B Munroe, Pier D Lambiase, Andrew Tinker and Michele Orini were supported by Medical Research Council grant MR/N025083/1. Julia Ramirez is funded by European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No.786833. Pier D Lambiase is supported by UCL/UCLH Biomedicine NIHR, Barts Heart Centre Biomedical Research Centre. Patricia B Munroe, Pier D Lambiase, Andrew Tinker and Helen Warren acknowledge the NIHR Cardiovascular Biomedical Centre at Barts and The London, Queen Mary University of London. Christopher Newton-Cheh acknowledges support from the National Institutes of Health (R01HL143070). The authors also wish to acknowledge the CHARGE infrastructure grant (HL105756).

Funding Information:
All study acknowledgements can be found in Supplementary Note 3 , and study funding information in Supplementary Note 4. William J Young was supported by an MRC grant MR/R017468/1. Alvaro Alonso is supported by an NHLBI award K24HL148521. Antonio Luiz P Ribeiro is supported in part by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17 and RED-00081-16). Eduardo Tarazona-Santos, Maria Fernanda Lima-Costa and Thiago P Leal are supported by Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq). Eduardo Tarazona-Santos and Maria Fernanda Lima-Costa are also supported by the Brazilian Ministry of Health (DECIT/MS, EPIGEN-Brazil Project), Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos (FINEP) and Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG). Ruth Loos is supported by the National Institutes of Health (R01DK110113; R01DK107786; R01HL142302; R01DK124097). Michael J Cutler is supported by funding from the Dell Loy Hansen Heart Foundation. M.Benjamin Shoemaker is supported by grant NIHK23HL127704. Rozenn Lemaitre reports funding from grant: AHA 19SFRN34830063. Steven A Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Patrick T Ellinor was supported by grants from Bayer AG, the Foundation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), and the American Heart Association (18SFRN34110082). Lu-Chen Weng was supported by National Institutes of Health (NIH) grant 1R01HL139731 and American Heart Association (AHA) grant 18SFRN34110082. Victor Nauffal is funded by a T32 training grant from the National Institutes of Health (5T32HL007604-35). Nona Sotoodehnia is supported by grants AHA19SFRN348300063, R01HL141989, Medic One Foundation, Laughlin Family. Ulrich Schotten received funding from the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hypercoagulability, Electrical remodelling, and Vascular Destabilization in the Progression of AF), the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286). Sébastien Thériault is supported by a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Québec-Santé (FRQS). Jonas L Isaksen is supported by CACHET. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). Christy Avery and Antoine Baldassari were supported by NIH grants R01HL142825, and U01HG007416. Dawood Darbar was supported by NIH grants R01HL138737 and T32HL139439. Daniel S Evans is supported by NIH grant U24AG051129. Niels Grarup is supported by the Novo Nordisk Foundation (Grant number NNF18CC0034900). James G. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Hao Mei is also supported by the CHARGE infrastructure grant (HL105756). Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). May E Montasser receives funding from Regeneron Pharmaceutical unrelated to this work. James F Wilson and Pau Navarro acknowledge support from the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). Linda Repetto is funded by a University of Edinburgh studentship. Xia Shen was in receipt of a Starting Grant (2017-02543) from the Swedish Research Council (Vetenskaprådet). Lars Lind is funded by Uppsala University Hospital, Uppsala, Sweden. Niek Verweij was supported by NWO VENI (016.186.125). Jan-Walter Benjamins is funded by the Research Project CVON-AI (2018B017) financed by the PPP Allowance made available by Top Sector Life Sciences & Health to the Dutch Heart Foundation to stimulate public-private partnerships. J.Wouter Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Oliver Hines is supported by a Medical Research Council DTP Studentship. Massimo Mangino is supported by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Patricia B Munroe, Pier D Lambiase, Andrew Tinker and Michele Orini were supported by Medical Research Council grant MR/N025083/1. Julia Ramirez is funded by European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No.786833. Pier D Lambiase is supported by UCL/UCLH Biomedicine NIHR, Barts Heart Centre Biomedical Research Centre. Patricia B Munroe, Pier D Lambiase, Andrew Tinker and Helen Warren acknowledge the NIHR Cardiovascular Biomedical Centre at Barts and The London, Queen Mary University of London. Christopher Newton-Cheh acknowledges support from the National Institutes of Health (R01HL143070). The authors also wish to acknowledge the CHARGE infrastructure grant (HL105756).

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