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, L. Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiß, Antoine 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, Álvaro 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 Peixoto Leal, Rozenn N. Lemaître, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. Macfarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Paré, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael Preuß, Olli T. Raitakari, Alex P. Reiner, Antônio Luiz Pinho Ribeiro
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.