Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

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...

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Vydané v:	Nature communications Ročník 13; číslo 1; s. 5144 - 18
Hlavní autori:	Isaacs, Aaron, Duong, ThuyVy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A., Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, 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, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Ryan, Kathleen A., Tarazona-Santos, Eduardo, van Duijvenboden, Stefan, Yao, Jie, Andreasen, Laura, Bis, Joshua C., Cutler, Michael J., Ellervik, Christina, Ellinor, Patrick T., Felix, Stephan B., Graff, Mariaelisa, Guo, Xiuqing, Heckbert, Susan R., Huang, Paul L., Hutri-Kähönen, Nina, Ikram, M. Arfan, Jackson, Rebecca D., Junttila, Juhani, Kavousi, Maryam, Kors, Jan A., Leal, Thiago P., Lemaitre, Rozenn N., Lind, Lars, Liu, Simin, MacFarlane, Peter W., Mangino, Massimo, Meitinger, Thomas, Mezzavilla, Massimo, Mishra, Pashupati P., Montasser, May E., Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K., Pelliccione, Giulia, Porteous, David J., Pramstaller, Peter P., Preuss, Michael H., Risch, Lorenz, Schurmann, Claudia, Sinner, Moritz F., Stoll, Monika, Tarasov, Kirill, Taylor, Kent D., Trompet, Stella, Uitterlinden, André, Völker, Uwe, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A., Wilson, James G., Avery, Christy L., Conen, David, Dörr, Marcus, Gharib, Sina A., Girotto, Giorgia, Grarup, Niels, Hayward, Caroline, Jamshidi, Yalda, Kähönen, Mika, Kanters, Jørgen K., Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J. F., Mook-Kanamori, Dennis O., Morris, Andrew P., O’Connell, Jeffrey R., Olesen, Morten Salling, Orini, Michele, Pattaro, Cristian, Psaty, Bruce M., Rotter, Jerome I., Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M., Arking, Dan E., Ramirez, Julia, Sotoodehnia, Nona, Munroe, Patricia B.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 01.09.2022 Nature Publishing Group Nature Portfolio
Predmet:	45 45/43 631/208/205/2138 631/208/721 Abnormalities Arrhythmia Arrhythmias, Cardiac - genetics Cardiac arrhythmia Cardiovascular diseases Connective tissues Coronary artery disease Death, Sudden, Cardiac Depolarization Electrocardiography - methods Energy metabolism Extracellular matrix Fibrillation Gene loci Genes Genetic analysis Genetic Testing Genomes Heart diseases Humanities and Social Sciences Humans Insulin Life Sciences Male multidisciplinary Science Science (multidisciplinary) Signal transduction Therapeutic applications Therapeutic targets Ventricle
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-32821-z