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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Published in:Nature communications Vol. 13; no. 1; pp. 5144 - 18
Main Authors: 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.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.09.2022
Nature Publishing Group
Nature Portfolio
Subjects:
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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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-32821-z