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Young, William J. ORCID logoORCID: https://orcid.org/0000-0002-9831-6817; Lahrouchi, Najim; Isaacs, Aaron ORCID logoORCID: https://orcid.org/0000-0001-5037-4834; Duong, ThuyVy; Foco, Luisa ORCID logoORCID: https://orcid.org/0000-0002-6694-3322; Ahmed, Farah; Brody, Jennifer A. ORCID logoORCID: https://orcid.org/0000-0001-8509-148X; Salman, Reem; Noordam, Raymond ORCID logoORCID: https://orcid.org/0000-0001-7801-809X; Benjamins, Jan-Walter ORCID logoORCID: https://orcid.org/0000-0002-5701-0539; Haessler, Jeffrey; Lyytikäinen, Leo-Pekka ORCID logoORCID: https://orcid.org/0000-0002-7200-5455; Repetto, Linda; Concas, Maria Pina ORCID logoORCID: https://orcid.org/0000-0003-3598-2537; Berg, Marten E. van den; Weiss, Stefan ORCID logoORCID: https://orcid.org/0000-0002-3553-4315; Baldassari, Antoine R.; Bartz, Traci M.; Cook, James P.; Evans, Daniel S.; Freudling, Rebecca; Hines, Oliver; Isaksen, Jonas L. ORCID logoORCID: https://orcid.org/0000-0003-3227-1131; Lin, Honghuang ORCID logoORCID: https://orcid.org/0000-0003-3043-3942; Mei, Hao; Moscati, Arden; Müller-Nurasyid, Martina ORCID logoORCID: https://orcid.org/0000-0003-3793-5910; Nursyifa, Casia; Qian, Yong; Richmond, Anne; Roselli, Carolina ORCID logoORCID: https://orcid.org/0000-0001-5267-6756; Ryan, Kathleen A. ORCID logoORCID: https://orcid.org/0000-0003-1158-8455; Tarazona-Santos, Eduardo; Thériault, Sébastien; Duijvenboden, Stefan van; Warren, Helen R. ORCID logoORCID: https://orcid.org/0000-0003-0511-1386; Yao, Jie; Raza, Dania; Aeschbacher, Stefanie; Ahlberg, Gustav; Alonso, Alvaro ORCID logoORCID: https://orcid.org/0000-0002-2225-8323; Andreasen, Laura ORCID logoORCID: https://orcid.org/0000-0002-4732-4921; Bis, Joshua C. ORCID logoORCID: https://orcid.org/0000-0002-3409-1110; Boerwinkle, Eric; Campbell, Archie ORCID logoORCID: https://orcid.org/0000-0003-0198-5078; Catamo, Eulalia; Cocca, Massimiliano ORCID logoORCID: https://orcid.org/0000-0002-1127-7596; Cutler, Michael J. ORCID logoORCID: https://orcid.org/0000-0001-9498-7472; Darbar, Dawood ORCID logoORCID: https://orcid.org/0000-0002-4103-5977; De Grandi, Alessandro; De Luca, Antonio; Ding, Jun; Ellervik, Christina ORCID logoORCID: https://orcid.org/0000-0002-3088-4375; Ellinor, Patrick T. ORCID logoORCID: https://orcid.org/0000-0002-2067-0533; Felix, Stephan B.; Froguel, Philippe ORCID logoORCID: https://orcid.org/0000-0003-2972-0784; Fuchsberger, Christian; Gögele, Martin ORCID logoORCID: https://orcid.org/0000-0003-4785-4348; Graff, Claus; Graff, Mariaelisa ORCID logoORCID: https://orcid.org/0000-0001-6380-1735; Guo, Xiuqing ORCID logoORCID: https://orcid.org/0000-0002-5264-5068; Hansen, Torben ORCID logoORCID: https://orcid.org/0000-0001-8748-3831; Heckbert, Susan R. ORCID logoORCID: https://orcid.org/0000-0002-7100-512X; Huang, Paul L.; Huikuri, Heikki V.; Hutri-Kähönen, Nina; Ikram, M. Arfan ORCID logoORCID: https://orcid.org/0000-0003-0372-8585; Jackson, Rebecca D.; Junttila, Juhani; Kavousi, Maryam ORCID logoORCID: https://orcid.org/0000-0001-5976-6519; Kors, Jan A.; Leal, Thiago P.; Lemaitre, Rozenn N. ORCID logoORCID: https://orcid.org/0000-0002-7038-1844; Lin, Henry J. ORCID logoORCID: https://orcid.org/0000-0001-6771-0486; Lind, Lars; Linneberg, Allan ORCID logoORCID: https://orcid.org/0000-0002-0994-0184; Liu, Simin ORCID logoORCID: https://orcid.org/0000-0003-2098-3844; MacFarlane, Peter W.; Mangino, Massimo ORCID logoORCID: https://orcid.org/0000-0002-2167-7470; Meitinger, Thomas ORCID logoORCID: https://orcid.org/0000-0002-8838-8403; Mezzavilla, Massimo ORCID logoORCID: https://orcid.org/0000-0002-9000-4595; Mishra, Pashupati P.; Mitchell, Rebecca N.; Mononen, Nina; Montasser, May E. ORCID logoORCID: https://orcid.org/0000-0002-9558-5456; Morrison, Alanna C. ORCID logoORCID: https://orcid.org/0000-0001-6381-4296; Nauck, Matthias ORCID logoORCID: https://orcid.org/0000-0002-6678-7964; Nauffal, Victor; Navarro, Pau ORCID logoORCID: https://orcid.org/0000-0001-5576-8584; Nikus, Kjell; Pare, Guillaume; Patton, Kristen K.; Pelliccione, Giulia; Pittman, Alan ORCID logoORCID: https://orcid.org/0000-0002-8112-2987; Porteous, David J. ORCID logoORCID: https://orcid.org/0000-0003-1249-6106; Pramstaller, Peter P. ORCID logoORCID: https://orcid.org/0000-0002-9831-8302; Preuss, Michael H. ORCID logoORCID: https://orcid.org/0000-0001-5266-8465; Raitakari, Olli T.; Reiner, Alexander P. ORCID logoORCID: https://orcid.org/0000-0002-1427-4470; Ribeiro, Antonio Luiz P. ORCID logoORCID: https://orcid.org/0000-0002-2740-0042; Rice, Kenneth M. ORCID logoORCID: https://orcid.org/0000-0002-3071-7278; Risch, Lorenz ORCID logoORCID: https://orcid.org/0000-0003-2692-6699; Schlessinger, David; Schotten, Ulrich; Schurmann, Claudia ORCID logoORCID: https://orcid.org/0000-0003-4158-9192; Shen, Xia ORCID logoORCID: https://orcid.org/0000-0003-4390-1979; Shoemaker, M. Benjamin; Sinagra, Gianfranco ORCID logoORCID: https://orcid.org/0000-0003-2700-8478; Sinner, Moritz F. ORCID logoORCID: https://orcid.org/0000-0002-6660-796X; Soliman, Elsayed Z. ORCID logoORCID: https://orcid.org/0000-0001-5632-8150; Stoll, Monika; Strauch, Konstantin; Tarasov, Kirill ORCID logoORCID: https://orcid.org/0000-0001-7799-4670; Taylor, Kent D.; Tinker, Andrew ORCID logoORCID: https://orcid.org/0000-0001-7703-4151; Trompet, Stella ORCID logoORCID: https://orcid.org/0000-0001-5006-0528; Uitterlinden, André ORCID logoORCID: https://orcid.org/0000-0002-7276-3387; Völker, Uwe; Völzke, Henry; Waldenberger, Melanie ORCID logoORCID: https://orcid.org/0000-0003-0583-5093; Weng, Lu-Chen ORCID logoORCID: https://orcid.org/0000-0003-1475-4930; Whitsel, Eric A. ORCID logoORCID: https://orcid.org/0000-0003-4843-3641; Wilson, James G.; Avery, Christy L. ORCID logoORCID: https://orcid.org/0000-0002-1044-8162; Conen, David; Correa, Adolfo ORCID logoORCID: https://orcid.org/0000-0002-9501-600X; Cucca, Francesco; Dörr, Marcus ORCID logoORCID: https://orcid.org/0000-0001-7471-475X; Gharib, Sina A.; Girotto, Giorgia ORCID logoORCID: https://orcid.org/0000-0003-4507-6589; Grarup, Niels ORCID logoORCID: https://orcid.org/0000-0001-5526-1070; Hayward, Caroline ORCID logoORCID: https://orcid.org/0000-0002-9405-9550; Jamshidi, Yalda ORCID logoORCID: https://orcid.org/0000-0003-0151-6482; Järvelin, Marjo-Riitta ORCID logoORCID: https://orcid.org/0000-0002-2149-0630; Jukema, J. Wouter ORCID logoORCID: https://orcid.org/0000-0002-3246-8359; Kääb, Stefan; Kähönen, Mika; Kanters, Jørgen K. ORCID logoORCID: https://orcid.org/0000-0002-3267-4910; Kooperberg, Charles ORCID logoORCID: https://orcid.org/0000-0002-7986-8560; Lehtimäki, Terho ORCID logoORCID: https://orcid.org/0000-0002-2555-4427; Lima-Costa, Maria Fernanda; Liu, Yongmei; Loos, Ruth J. F. ORCID logoORCID: https://orcid.org/0000-0002-8532-5087; Lubitz, Steven A. ORCID logoORCID: https://orcid.org/0000-0002-9599-4866; Mook-Kanamori, Dennis O.; Morris, Andrew P. ORCID logoORCID: https://orcid.org/0000-0002-6805-6014; O’Connell, Jeffrey R.; Olesen, Morten Salling ORCID logoORCID: https://orcid.org/0000-0001-9477-5322; Orini, Michele ORCID logoORCID: https://orcid.org/0000-0001-5773-0344; Padmanabhan, Sandosh; Pattaro, Cristian ORCID logoORCID: https://orcid.org/0000-0002-4119-0109; Peters, Annette ORCID logoORCID: https://orcid.org/0000-0001-6645-0985; Psaty, Bruce M. ORCID logoORCID: https://orcid.org/0000-0002-7278-2190; Rotter, Jerome I.; Stricker, Bruno; Harst, Pim van der ORCID logoORCID: https://orcid.org/0000-0002-2713-686X; Duijn, Cornelia M. van ORCID logoORCID: https://orcid.org/0000-0002-2374-9204; Verweij, Niek ORCID logoORCID: https://orcid.org/0000-0002-4303-7685; Wilson, James F. ORCID logoORCID: https://orcid.org/0000-0001-5751-9178; Arking, Dan E.; Ramirez, Julia ORCID logoORCID: https://orcid.org/0000-0003-4130-5866; Lambiase, Pier D.; Sotoodehnia, Nona; Mifsud, Borbala; Newton-Cheh, Christopher ORCID logoORCID: https://orcid.org/0000-0002-3001-9111 and Munroe, Patricia B. ORCID logoORCID: https://orcid.org/0000-0002-4176-2947 (2022): Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. In: Nature Communications, Vol. 13, 5144 [PDF, 3MB]


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.

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