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. 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 F. 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, 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

Genomics and Translational Biomedicine

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

20 Citations (Scopus)

Abstract

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.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
Number of pages	18
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

Atrial-fibrillation
Corrected qt
Disease
Genome-wide association
Heart
Prolongation
Qrs duration
Risk
Sex-differences
Sudden cardiac death

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10.1038/s41467-022-32821-z

Cite this

Young, W. J., Lahrouchi, N., Isaacs, A., Duong, T. V., 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., ... 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{fc9c241fcf234434bf3d83ddbe51a50e,

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

abstract = "The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.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 = "Atrial-fibrillation, Corrected qt, Disease, Genome-wide association, Heart, Prolongation, Qrs duration, Risk, Sex-differences, Sudden cardiac death",

author = "Young, {William J.} and Najim Lahrouchi and Aaron Isaacs and Duong, {Thuy Vy} and Luisa Foco and Farah Ahmed and Brody, {Jennifer A.} and Reem Salman and Raymond Noordam and Benjamins, {Jan Walter} and Jeffrey Haessler and Lyytik{\"a}inen, {Leo Pekka} 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 Weng, {Lu Chen} 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 J{\"a}rvelin, {Marjo Riitta} 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 F.} 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 = "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 Research",

number = "1",

}

Young, WJ, Lahrouchi, N, Isaacs, A, Duong, TV, Foco, L, Ahmed, F, Brody, JA, Salman, R, Noordam, R, Benjamins, JW, Haessler, J, Lyytikäinen, LP, 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, LC, 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, MR, 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, JF, 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, Thuy Vy

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 F.

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.

PY - 2022/9/1

Y1 - 2022/9/1

N2 - The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.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 a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.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 - Atrial-fibrillation

KW - Corrected qt

KW - Disease

KW - Genome-wide association

KW - Heart

KW - Prolongation

KW - Qrs duration

KW - Risk

KW - Sex-differences

KW - Sudden cardiac death

UR - http://www.scopus.com/inward/record.url?scp=85137092502&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-32821-z

DO - 10.1038/s41467-022-32821-z

M3 - Article

C2 - 36050321

AN - SCOPUS:85137092502

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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