Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization
Authors: Young William J. , Lahrouchi Najim , Isaacs Aaron , Duong ThuyVy , Foco Luisa , Ahmed Farah , Brody Jennifer A. , Salman Reem , Noordam Raymond , Benjamins Jan-Walter , Haessler Jeffrey , Lyytikäinen Leo-Pekka , Repetto Linda , Concas Maria Pina , van den Berg Marten E. , Weiss Stefan , Baldassari Antoine R. , Bartz Traci M. , Cook James P. , Evans Daniel S. , Freudling Rebecca , Hines Oliver , Isaksen Jonas L. , Lin Honghuang , Mei Hao , Moscati Arden , Müller-Nurasyid Martina , Nursyifa Casia , Qian Yong , Richmond Anne , Roselli Carolina , Ryan Kathleen A. , Tarazona-Santos Eduardo , Thériault Sébastien , van Duijvenboden Stefan , Warren Helen R. , Yao Jie , Raza Dania , Aeschbacher Stefanie , Ahlberg Gustav , Alonso Alvaro , Andreasen Laura , Bis Joshua C. , Boerwinkle Eric , Campbell Archie , Catamo Eulalia , Cocca Massimiliano , Cutler Michael J. , Darbar Dawood , De Grandi Alessandro , De Luca Antonio , Ding Jun , Ellervik Christina , Ellinor Patrick T. , Felix Stephan B. , Froguel Philippe , Fuchsberger Christian , Gögele Martin , Graff Claus , Graff Mariaelisa , Guo Xiuqing , Hansen Torben , Heckbert Susan R. , Huang Paul L. , Huikuri Heikki V. , Hutri-Kähönen Nina , Ikram M.Arfan , Jackson Rebecca D. , Junttila Juhani , Kavousi Maryam , Kors Jan A. , Leal Thiago P. , Lemaitre Rozenn N. , Lin Henry J. , Lind Lars , Linneberg Allan , Liu Simin , MacFarlane Peter W. , Mangino Massimo , Meitinger Thomas , Mezzavilla Massimo , Mishra Pashupati P. , Mitchell Rebecca N. , Mononen Nina , Montasser May E. , Morrison Alanna C. , Nauck Matthias , Nauffal Victor , Navarro Pau , Nikus Kjell , Pare Guillaume , Patton Kristen K. , Pelliccione Giulia , Pittman Alan , Porteous David J. , Pramstaller Peter P. , Preuss Michael H. , Raitakari Olli T. , Reiner Alexander P. , Ribeiro Antonio Luiz P. , Rice Kenneth M. , Risch Lorenz , Schlessinger David , Schotten Ulrich , Schurmann Claudia , Shen Xia , Shoemaker M.Benjamin , Sinagra Gianfranco , Sinner Moritz F. , Soliman Elsayed Z. , Stoll Monika , Strauch Konstantin , Tarasov Kirill , Taylor Kent D. , Tinker Andrew , Trompet Stella , Uitterlinden André , Völker Uwe , Völzke Henry , Waldenberger Melanie , Weng Lu-Chen , Whitsel Eric A. , Wilson James G. , Avery Christy L. , Conen David , Correa Adolfo , Cucca Francesco , Dörr Marcus , Gharib Sina A. , Girotto Giorgia , Grarup Niels , Hayward Caroline , Jamshidi Yalda , Järvelin Marjo-Riitta , Jukema J.Wouter , Kääb Stefan , Kähönen Mika , Kanters Jørgen K. , Kooperberg Charles , Lehtimäki Terho , Lima-Costa Maria Fernanda , Liu Yongmei , Loos Ruth J.F. , Lubitz Steven A. , Mook-Kanamori Dennis O. , Morris Andrew P. , O’Connell Jeffrey R. , Olesen Morten Salling , Orini Michele , Padmanabhan Sandosh , Pattaro Cristian , Peters Annette , Psaty Bruce M. , Rotter Jerome I. , Stricker Bruno , van der Harst Pim , van Duijn Cornelia M. , Verweij Niek , Wilson James F. , Arking Dan E. , Ramirez Julia , Lambiase Pier D. , Sotoodehnia Nona , Mifsud Borbala , Newton-Cheh Christopher , Munroe Patricia B. 
Published: November 2021

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 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 identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.