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