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. Van Den 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 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 G. Wilson; Dan E. Arking; Julia Ramirez; Pier D. Lambiase; Nona Sotoodehnia; Borbala Mifsud; Christopher Newton-cheh; Patricia B. Munroe

doi:10.1038/s41467-022-32821-z

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. 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 G. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-cheh, Patricia B. Munroe

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 language	English
Article number	5144
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32821-z
Publication status	Published - 1 Sept 2022

Keywords / Materials (for Non-textual outputs)

Arrhythmias, Cardiac/genetics
Death, Sudden, Cardiac
Electrocardiography/methods
Genetic Testing
Humans
Male

Access to Document

10.1038/s41467-022-32821-z

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways_QT_Manuscript main file_finalrevisionAccepted author manuscript, 262 KB
Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathwaysFinal published version, 3.68 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.nature.com/articles/s41467-022-32821-z

Cite this

Young, W. J., Lahrouchi, N., Isaacs, A., Duong, T., Foco, L., Ahmed, F., Brody, J. A., Salman, R., Noordam, R., Benjamins, J., Haessler, J., Lyytikäinen, L., Repetto, L., Concas, M. P., Van Den Berg, M. E., Weiss, S., Baldassari, A. R., Bartz, T. M., Cook, J. P., ... Munroe, P. B. (2022). Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. Nature Communications, 13(1), Article 5144. https://doi.org/10.1038/s41467-022-32821-z

@article{9d8869f720f14f09a454c03238f7cf9d,

title = "Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways",

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.",

keywords = "Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac, Electrocardiography/methods, Genetic Testing, Humans, Male",

author = "Young, {William J.} and Najim Lahrouchi and Aaron Isaacs and Thuyvy Duong and Luisa Foco and Farah Ahmed and Brody, {Jennifer A.} and Reem Salman and Raymond Noordam and Jan-walter Benjamins and Jeffrey Haessler and Leo-pekka Lyytik{\"a}inen and Linda Repetto and Concas, {Maria Pina} and {Van Den Berg}, {Marten E.} and Stefan Weiss and Baldassari, {Antoine R.} and Bartz, {Traci M.} and Cook, {James P.} and Evans, {Daniel S.} and Rebecca Freudling and Oliver Hines and Isaksen, {Jonas L.} and Honghuang Lin and Hao Mei and Arden Moscati and Martina M{\"u}ller-nurasyid and Casia Nursyifa and Yong Qian and Anne Richmond and Carolina Roselli and Ryan, {Kathleen A.} and Eduardo Tarazona-santos and S{\'e}bastien Th{\'e}riault and {Van Duijvenboden}, Stefan and Warren, {Helen R.} and Jie Yao and Dania Raza and Stefanie Aeschbacher and Gustav Ahlberg and Alvaro Alonso and Laura Andreasen and Bis, {Joshua C.} and Eric Boerwinkle and Archie Campbell and Eulalia Catamo and Massimiliano Cocca and Cutler, {Michael J.} and Dawood Darbar and {De Grandi}, Alessandro and {De Luca}, Antonio and Jun Ding and Christina Ellervik and Ellinor, {Patrick T.} and Felix, {Stephan B.} and Philippe Froguel and Christian Fuchsberger and Martin G{\"o}gele and Claus Graff and Mariaelisa Graff and Xiuqing Guo and Torben Hansen and Heckbert, {Susan R.} and Huang, {Paul L.} and Huikuri, {Heikki V.} and Nina Hutri-k{\"a}h{\"o}nen and Ikram, {M. Arfan} and Jackson, {Rebecca D.} and Juhani Junttila and Maryam Kavousi and Kors, {Jan A.} and Leal, {Thiago P.} and Lemaitre, {Rozenn N.} and Lin, {Henry J.} and Lars Lind and Allan Linneberg and Simin Liu and Macfarlane, {Peter W.} and Massimo Mangino and Thomas Meitinger and Massimo Mezzavilla and Mishra, {Pashupati P.} and Mitchell, {Rebecca N.} and Nina Mononen and Montasser, {May E.} and Morrison, {Alanna C.} and Matthias Nauck and Victor Nauffal and Pau Navarro and Kjell Nikus and Guillaume Pare and Patton, {Kristen K.} and Giulia Pelliccione and Alan Pittman and Porteous, {David J.} and Pramstaller, {Peter P.} and Preuss, {Michael H.} and Raitakari, {Olli T.} and Reiner, {Alexander P.} and Ribeiro, {Antonio Luiz P.} and Rice, {Kenneth M.} and Lorenz Risch and David Schlessinger and Ulrich Schotten and Claudia Schurmann and Xia Shen and Shoemaker, {M. Benjamin} and Gianfranco Sinagra and Sinner, {Moritz F.} and Soliman, {Elsayed Z.} and Monika Stoll and Konstantin Strauch and Kirill Tarasov and Taylor, {Kent D.} and Andrew Tinker and Stella Trompet and Andr{\'e} Uitterlinden and Uwe V{\"o}lker and Henry V{\"o}lzke and Melanie Waldenberger and Lu-chen Weng and Whitsel, {Eric A.} and Wilson, {James G.} and Avery, {Christy L.} and David Conen and Adolfo Correa and Francesco Cucca and Marcus D{\"o}rr and Gharib, {Sina A.} and Giorgia Girotto and Niels Grarup and Caroline Hayward and Yalda Jamshidi and Marjo-riitta J{\"a}rvelin and Jukema, {J. Wouter} and Stefan K{\"a}{\"a}b and Mika K{\"a}h{\"o}nen and Kanters, {J{\o}rgen K.} and Charles Kooperberg and Terho Lehtim{\"a}ki and Lima-costa, {Maria Fernanda} and Yongmei Liu and Loos, {Ruth J. F.} and Lubitz, {Steven A.} and Mook-kanamori, {Dennis O.} and Morris, {Andrew P.} and O{\textquoteright}connell, {Jeffrey R.} and Olesen, {Morten Salling} and Michele Orini and Sandosh Padmanabhan and Cristian Pattaro and Annette Peters and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Bruno Stricker and {Van Der Harst}, Pim and {Van Duijn}, {Cornelia M.} and Niek Verweij and Wilson, {James G.} and Arking, {Dan E.} and Julia Ramirez and Lambiase, {Pier D.} and Nona Sotoodehnia and Borbala Mifsud and Christopher Newton-cheh and Munroe, {Patricia B.}",

note = "Funding Information: M.J.C. has consulted for Biosense Webster and Janssen Scientific. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. P.T.E. has received grant funding from Bayer AG and served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.O.M.-K. is a part time research consultant at Metabolon, Inc. D.C has received speaker fees from BMS/Pfizer and consultation fees from Roche Diagnostics. U.S received consultancy fees or honoraria from Universit{\`a} della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions Inc. (Switzerland), Johnson & Johnson Medical Limited, (United Kingdom), Bayer Healthcare (Germany). U.S is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht. L.-C.W receives sponsored research support from IBM to the Broad Institute. The remaining authors declare no competing interests. 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 Cient{\'i}fico 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 Funda{\c c}{\~a}o 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). S{\'e}bastien Th{\'e}riault is supported by a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Qu{\'e}bec-Sant{\'e} (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 (Vetenskapr{\aa}det). 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{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

day = "1",

doi = "10.1038/s41467-022-32821-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Young, WJ, Lahrouchi, N, Isaacs, A, Duong, T, Foco, L, Ahmed, F, Brody, JA, Salman, R, Noordam, R, Benjamins, J, Haessler, J, Lyytikäinen, L, Repetto, L, Concas, MP, Van Den Berg, ME, Weiss, S, Baldassari, AR, Bartz, TM, Cook, JP, Evans, DS, Freudling, R, Hines, O, Isaksen, JL, Lin, H, Mei, H, Moscati, A, Müller-nurasyid, M, Nursyifa, C, Qian, Y, Richmond, A, Roselli, C, Ryan, KA, Tarazona-santos, E, Thériault, S, Van Duijvenboden, S, Warren, HR, Yao, J, Raza, D, Aeschbacher, S, Ahlberg, G, Alonso, A, Andreasen, L, Bis, JC, Boerwinkle, E, Campbell, A, Catamo, E, Cocca, M, Cutler, MJ, Darbar, D, De Grandi, A, De Luca, A, Ding, J, Ellervik, C, Ellinor, PT, Felix, SB, Froguel, P, Fuchsberger, C, Gögele, M, Graff, C, Graff, M, Guo, X, Hansen, T, Heckbert, SR, Huang, PL, Huikuri, HV, Hutri-kähönen, N, Ikram, MA, Jackson, RD, Junttila, J, Kavousi, M, Kors, JA, Leal, TP, Lemaitre, RN, Lin, HJ, Lind, L, Linneberg, A, Liu, S, Macfarlane, PW, Mangino, M, Meitinger, T, Mezzavilla, M, Mishra, PP, Mitchell, RN, Mononen, N, Montasser, ME, Morrison, AC, Nauck, M, Nauffal, V, Navarro, P, Nikus, K, Pare, G, Patton, KK, Pelliccione, G, Pittman, A, Porteous, DJ, Pramstaller, PP, Preuss, MH, Raitakari, OT, Reiner, AP, Ribeiro, ALP, Rice, KM, Risch, L, Schlessinger, D, Schotten, U, Schurmann, C, Shen, X, Shoemaker, MB, Sinagra, G, Sinner, MF, Soliman, EZ, Stoll, M, Strauch, K, Tarasov, K, Taylor, KD, Tinker, A, Trompet, S, Uitterlinden, A, Völker, U, Völzke, H, Waldenberger, M, Weng, L, Whitsel, EA, Wilson, JG, Avery, CL, Conen, D, Correa, A, Cucca, F, Dörr, M, Gharib, SA, Girotto, G, Grarup, N, Hayward, C, Jamshidi, Y, Järvelin, M, Jukema, JW, Kääb, S, Kähönen, M, Kanters, JK, Kooperberg, C, Lehtimäki, T, Lima-costa, MF, Liu, Y, Loos, RJF, Lubitz, SA, Mook-kanamori, DO, Morris, AP, O’connell, JR, Olesen, MS, Orini, M, Padmanabhan, S, Pattaro, C, Peters, A, Psaty, BM, Rotter, JI, Stricker, B, Van Der Harst, P, Van Duijn, CM, Verweij, N, Wilson, JG, Arking, DE, Ramirez, J, Lambiase, PD, Sotoodehnia, N, Mifsud, B, Newton-cheh, C & Munroe, PB 2022, 'Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways', Nature Communications, vol. 13, no. 1, 5144. https://doi.org/10.1038/s41467-022-32821-z

TY - JOUR

T1 - Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

AU - Young, William J.

AU - Lahrouchi, Najim

AU - Isaacs, Aaron

AU - Duong, Thuyvy

AU - Foco, Luisa

AU - Ahmed, Farah

AU - Brody, Jennifer A.

AU - Salman, Reem

AU - Noordam, Raymond

AU - Benjamins, Jan-walter

AU - Haessler, Jeffrey

AU - Lyytikäinen, Leo-pekka

AU - Repetto, Linda

AU - Concas, Maria Pina

AU - Van Den Berg, Marten E.

AU - Weiss, Stefan

AU - Baldassari, Antoine R.

AU - Bartz, Traci M.

AU - Cook, James P.

AU - Evans, Daniel S.

AU - Freudling, Rebecca

AU - Hines, Oliver

AU - Isaksen, Jonas L.

AU - Lin, Honghuang

AU - Mei, Hao

AU - Moscati, Arden

AU - Müller-nurasyid, Martina

AU - Nursyifa, Casia

AU - Qian, Yong

AU - Richmond, Anne

AU - Roselli, Carolina

AU - Ryan, Kathleen A.

AU - Tarazona-santos, Eduardo

AU - Thériault, Sébastien

AU - Van Duijvenboden, Stefan

AU - Warren, Helen R.

AU - Yao, Jie

AU - Raza, Dania

AU - Aeschbacher, Stefanie

AU - Ahlberg, Gustav

AU - Alonso, Alvaro

AU - Andreasen, Laura

AU - Bis, Joshua C.

AU - Boerwinkle, Eric

AU - Campbell, Archie

AU - Catamo, Eulalia

AU - Cocca, Massimiliano

AU - Cutler, Michael J.

AU - Darbar, Dawood

AU - De Grandi, Alessandro

AU - De Luca, Antonio

AU - Ding, Jun

AU - Ellervik, Christina

AU - Ellinor, Patrick T.

AU - Felix, Stephan B.

AU - Froguel, Philippe

AU - Fuchsberger, Christian

AU - Gögele, Martin

AU - Graff, Claus

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Hansen, Torben

AU - Heckbert, Susan R.

AU - Huang, Paul L.

AU - Huikuri, Heikki V.

AU - Hutri-kähönen, Nina

AU - Ikram, M. Arfan

AU - Jackson, Rebecca D.

AU - Junttila, Juhani

AU - Kavousi, Maryam

AU - Kors, Jan A.

AU - Leal, Thiago P.

AU - Lemaitre, Rozenn N.

AU - Lin, Henry J.

AU - Lind, Lars

AU - Linneberg, Allan

AU - Liu, Simin

AU - Macfarlane, Peter W.

AU - Mangino, Massimo

AU - Meitinger, Thomas

AU - Mezzavilla, Massimo

AU - Mishra, Pashupati P.

AU - Mitchell, Rebecca N.

AU - Mononen, Nina

AU - Montasser, May E.

AU - Morrison, Alanna C.

AU - Nauck, Matthias

AU - Nauffal, Victor

AU - Navarro, Pau

AU - Nikus, Kjell

AU - Pare, Guillaume

AU - Patton, Kristen K.

AU - Pelliccione, Giulia

AU - Pittman, Alan

AU - Porteous, David J.

AU - Pramstaller, Peter P.

AU - Preuss, Michael H.

AU - Raitakari, Olli T.

AU - Reiner, Alexander P.

AU - Ribeiro, Antonio Luiz P.

AU - Rice, Kenneth M.

AU - Risch, Lorenz

AU - Schlessinger, David

AU - Schotten, Ulrich

AU - Schurmann, Claudia

AU - Shen, Xia

AU - Shoemaker, M. Benjamin

AU - Sinagra, Gianfranco

AU - Sinner, Moritz F.

AU - Soliman, Elsayed Z.

AU - Stoll, Monika

AU - Strauch, Konstantin

AU - Tarasov, Kirill

AU - Taylor, Kent D.

AU - Tinker, Andrew

AU - Trompet, Stella

AU - Uitterlinden, André

AU - Völker, Uwe

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Weng, Lu-chen

AU - Whitsel, Eric A.

AU - Wilson, James G.

AU - Avery, Christy L.

AU - Conen, David

AU - Correa, Adolfo

AU - Cucca, Francesco

AU - Dörr, Marcus

AU - Gharib, Sina A.

AU - Girotto, Giorgia

AU - Grarup, Niels

AU - Hayward, Caroline

AU - Jamshidi, Yalda

AU - Järvelin, Marjo-riitta

AU - Jukema, J. Wouter

AU - Kääb, Stefan

AU - Kähönen, Mika

AU - Kanters, Jørgen K.

AU - Kooperberg, Charles

AU - Lehtimäki, Terho

AU - Lima-costa, Maria Fernanda

AU - Liu, Yongmei

AU - Loos, Ruth J. F.

AU - Lubitz, Steven A.

AU - Mook-kanamori, Dennis O.

AU - Morris, Andrew P.

AU - O’connell, Jeffrey R.

AU - Olesen, Morten Salling

AU - Orini, Michele

AU - Padmanabhan, Sandosh

AU - Pattaro, Cristian

AU - Peters, Annette

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Stricker, Bruno

AU - Van Der Harst, Pim

AU - Van Duijn, Cornelia M.

AU - Verweij, Niek

AU - Wilson, James G.

AU - Arking, Dan E.

AU - Ramirez, Julia

AU - Lambiase, Pier D.

AU - Sotoodehnia, Nona

AU - Mifsud, Borbala

AU - Newton-cheh, Christopher

AU - Munroe, Patricia B.

N1 - Funding Information: M.J.C. has consulted for Biosense Webster and Janssen Scientific. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. P.T.E. has received grant funding from Bayer AG and served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.O.M.-K. is a part time research consultant at Metabolon, Inc. D.C has received speaker fees from BMS/Pfizer and consultation fees from Roche Diagnostics. U.S received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions Inc. (Switzerland), Johnson & Johnson Medical Limited, (United Kingdom), Bayer Healthcare (Germany). U.S is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht. L.-C.W receives sponsored research support from IBM to the Broad Institute. The remaining authors declare no competing interests. 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). Publisher Copyright: © 2022, The Author(s).

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

KW - Arrhythmias, Cardiac/genetics

KW - Death, Sudden, Cardiac

KW - Electrocardiography/methods

KW - Genetic Testing

KW - Humans

KW - Male

U2 - 10.1038/s41467-022-32821-z

DO - 10.1038/s41467-022-32821-z

M3 - Article

C2 - 36050321

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5144

ER -

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

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