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, Laura Andreasen, Christina Ellervik, Torben Hansen, Rebecca D Jackson, Lars Lind, Allan Linneberg, Niels Grarup, Jørgen K Kanters, Ruth J F Loos, Morten Salling Olesen, CHARGE Consortium

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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.

OriginalsprogEngelsk
Artikelnummer5144
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Antal sider18
ISSN2041-1723
DOI
StatusUdgivet - 2022

Bibliografisk note

© 2022. The Author(s).

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