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; Michele Orini

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, Michele Orini

Biomedical Engineering Department

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

18 Citations (Scopus)

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 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 - Dec 2022

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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., ... Orini, M. (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{05815573e80747f6968c745d9e04843c,

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.",

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 Michele Orini",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

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 & Orini, M 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 - Orini, Michele

PY - 2022/12

Y1 - 2022/12

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.

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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