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

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Title: Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
Authors: Young, William J., Author, Lahrouchi, Najim, Author, Isaacs, Aaron, Author, Duong, Thuy Vy, Author, Foco, Luisa, Author, Ahmed, Farah, Author, Brody, Jennifer A., Author, Salman, Reem, Author, Noordam, Raymond, Author, Benjamins, Jan-Walter, Author, Haessler, Jeffrey, Author, Lyytikainen, Leo-Pekka, Author, Repetto, Linda, Author, Concas, Maria Pina, Author, van den Berg, Marten E., Author, Weiss, Stefan, Author, Baldassari, Antoine R., Author, Bartz, Traci M., Author, Cook, James P., Author, Evans, Daniel S., Author, Freudling, Rebecca, Author, Hines, Oliver, Author, Isaksen, Jonas L., Author, Lin, Honghuang, Author, Mei, Hao, Author, Moscati, Arden, Author, Mueller-Nurasyid, Martina, Author, Nursyifa, Casia, Author, Qian, Yong, Author, Richmond, Anne, Author, Roselli, Carolina, Author, Ryan, Kathleen A., Author, Tarazona-Santos, Eduardo, Author, Theriault, Sebastien, Author, van Duijvenboden, Stefan, Author, Warren, Helen R., Author, Yao, Jie, Author, Raza, Dania, Author, Aeschbacher, Stefanie, Author, Ahlberg, Gustav, Author, Alonso, Alvaro, Author, Andreasen, Laura, Author, Bis, Joshua C., Author, Boerwinkle, Eric, Author, Campbell, Archie, Author, Catamo, Eulalia, Author, Cocca, Massimiliano, Author, Cutler, Michael J., Author, Darbar, Dawood, Author, De Grandi, Alessandro, Author, De Luca, Antonio, Author, Ding, Jun, Author, Ellervik, Christina, Author, Ellinor, Patrick T., Author, Felix, Stephan B., Author, Froguel, Philippe, Author, Fuchsberger, Christian, Author, Gogele, Martin, Author, Graff, Claus, Author, Graff, Mariaelisa, Author, Guo, Xiuqing, Author, Hansen, Torben, Author, Heckbert, Susan R., Author, Huang, Paul L., Author, Huikuri, Heikki, V, Author, Hutri-Kahonen, Nina, Author, Ikram, M. Arfan, Author, Jackson, Rebecca D., Author, Junttila, Juhani, Author, Kavousi, Maryam, Author, Kors, Jan A., Author, Leal, Thiago P., Author, Lemaitre, Rozenn N., Author, Lin, Henry J., Author, Lind, Lars, Author, Linneberg, Allan, Author, Liu, Simin, Author, MacFarlane, Peter W., Author, Mangino, Massimo, Author, Meitinger, Thomas, Author, Mezzavilla, Massimo, Author, Mishra, Pashupati P., Author, Mitchell, Rebecca N., Author, Mononen, Nina, Author, Montasser, May E., Author, Morrison, Alanna C., Author, Nauck, Matthias, Author, Nauffal, Victor, Author, Navarro, Pau, Author, Nikus, Kjell, Author, Pare, Guillaume, Author, Patton, Kristen K., Author, Pelliccione, Giulia, Author, Pittman, Alan, Author, Porteous, David J., Author, Pramstaller, Peter P., Author, Preuss, Michael H., Author, Raitakari, Olli T., Author, Reiner, Alexander P., Author, Ribeiro, Antonio Luiz P., Author, Rice, Kenneth M., Author, Risch, Lorenz, Author, Schlessinger, David, Author, Schotten, Ulrich, Author, Schurmann, Claudia, Author, Shen, Xia, Author, Shoemaker, M. Benjamin, Author, Sinagra, Gianfranco, Author, Sinner, Moritz F., Author, Soliman, Elsayed Z., Author, Stoll, Monika, Author, Strauch, Konstantin, Author, Tarasov, Kirill, Author, Taylor, Kent D., Author, Tinker, Andrew, Author, Trompet, Stella, Author, Uitterlinden, Andre, Author, Voelker, Uwe, Author, Voelzke, Henry, Author, Waldenberger, Melanie, Author, Weng, Lu-Chen, Author, Whitsel, Eric A., Author, Wilson, James G., Author, Avery, Christy L., Author, Conen, David, Author, Correa, Adolfo, Author, Cucca, Francesco, Author, Dorr, Marcus, Author, Gharib, Sina A., Author, Girotto, Giorgia, Author, Grarup, Niels, Author, Hayward, Caroline, Author, Jamshidi, Yalda, Author, Jarvelin, Marjo-Riitta, Author, Jukema, J. Wouter, Author, Kaab, Stefan, Author, Kahonen, Mika, Author, Kanters, Jorgen K., Author, Kooperberg, Charles, Author, Lehtimaki, Terho, Author, Lima-Costa, Maria Fernanda, Author, Liu, Yongmei, Author, Loos, Ruth J. F., Author, Lubitz, Steven A., Author, Mook-Kanamori, Dennis O., Author, Morris, Andrew P., Author, O'Connell, Jeffrey R., Author, Olesen, Morten Salling, Author, Orini, Michele, Author, Padmanabhan, Sandosh, Author, Pattaro, Cristian, Author, Peters, Annette, Author, Psaty, Bruce M., Author, Rotter, Jerome, I, Author, Stricker, Bruno, Author, van der Harst, Pim, Author, van Duijn, Cornelia M., Author, Verweij, Niek, Author, Wilson, James F., Author, Arking, Dan E., Author, Ramirez, Julia, Author, Lambiase, Pier D., Author, Sotoodehnia, Nona, Author, Mifsud, Borbala, Author, Newton-Cheh, Christopher, Author, Munroe, Patricia B., Author
Contributors: Young, William J., Author, Lahrouchi, Najim, Author, Isaacs, Aaron, Author, Duong, Thuy Vy, Author, Foco, Luisa, Author, Ahmed, Farah, Author, Brody, Jennifer A., Author, Salman, Reem, Author, Noordam, Raymond, Author, Benjamins, Jan-Walter, Author, Haessler, Jeffrey, Author, Lyytikainen, Leo-Pekka, Author, Repetto, Linda, Author, Concas, Maria Pina, Author, van den Berg, Marten E., Author, Weiss, Stefan, Author, Baldassari, Antoine R., Author, Bartz, Traci M., Author, Cook, James P., Author, Evans, Daniel S., Author, Freudling, Rebecca, Author, Hines, Oliver, Author, Isaksen, Jonas L., Author, Lin, Honghuang, Author, Mei, Hao, Author, Moscati, Arden, Author, Mueller-Nurasyid, Martina, Author, Nursyifa, Casia, Author, Qian, Yong, Author, Richmond, Anne, Author, Roselli, Carolina, Author, Ryan, Kathleen A., Author, Tarazona-Santos, Eduardo, Author, Theriault, Sebastien, Author, van Duijvenboden, Stefan, Author, Warren, Helen R., Author, Yao, Jie, Author, Raza, Dania, Author, Aeschbacher, Stefanie, Author, Ahlberg, Gustav, Author, Alonso, Alvaro, Author, Andreasen, Laura, Author, Bis, Joshua C., Author, Boerwinkle, Eric, Author, Campbell, Archie, Author, Catamo, Eulalia, Author, Cocca, Massimiliano, Author, Cutler, Michael J., Author, Darbar, Dawood, Author, De Grandi, Alessandro, Author, De Luca, Antonio, Author, Ding, Jun, Author, Ellervik, Christina, Author, Ellinor, Patrick T., Author, Felix, Stephan B., Author, Froguel, Philippe, Author, Fuchsberger, Christian, Author, Gogele, Martin, Author, Graff, Claus, Author, Graff, Mariaelisa, Author, Guo, Xiuqing, Author, Hansen, Torben, Author, Heckbert, Susan R., Author, Huang, Paul L., Author, Huikuri, Heikki, V, Author, Hutri-Kahonen, Nina, Author, Ikram, M. Arfan, Author, Jackson, Rebecca D., Author, Junttila, Juhani, Author, Kavousi, Maryam, Author, Kors, Jan A., Author, Leal, Thiago P., Author, Lemaitre, Rozenn N., Author, Lin, Henry J., Author, Lind, Lars, Author, Linneberg, Allan, Author, Liu, Simin, Author, MacFarlane, Peter W., Author, Mangino, Massimo, Author, Meitinger, Thomas, Author, Mezzavilla, Massimo, Author, Mishra, Pashupati P., Author, Mitchell, Rebecca N., Author, Mononen, Nina, Author, Montasser, May E., Author, Morrison, Alanna C., Author, Nauck, Matthias, Author, Nauffal, Victor, Author, Navarro, Pau, Author, Nikus, Kjell, Author, Pare, Guillaume, Author, Patton, Kristen K., Author, Pelliccione, Giulia, Author, Pittman, Alan, Author, Porteous, David J., Author, Pramstaller, Peter P., Author, Preuss, Michael H., Author, Raitakari, Olli T., Author, Reiner, Alexander P., Author, Ribeiro, Antonio Luiz P., Author, Rice, Kenneth M., Author, Risch, Lorenz, Author, Schlessinger, David, Author, Schotten, Ulrich, Author, Schurmann, Claudia, Author, Shen, Xia, Author, Shoemaker, M. Benjamin, Author, Sinagra, Gianfranco, Author, Sinner, Moritz F., Author, Soliman, Elsayed Z., Author, Stoll, Monika, Author, Strauch, Konstantin, Author, Tarasov, Kirill, Author, Taylor, Kent D., Author, Tinker, Andrew, Author, Trompet, Stella, Author, Uitterlinden, Andre, Author, Voelker, Uwe, Author, Voelzke, Henry, Author, Waldenberger, Melanie, Author, Weng, Lu-Chen, Author, Whitsel, Eric A., Author, Wilson, James G., Author, Avery, Christy L., Author, Conen, David, Author, Correa, Adolfo, Author, Cucca, Francesco, Author, Dorr, Marcus, Author, Gharib, Sina A., Author, Girotto, Giorgia, Author, Grarup, Niels, Author, Hayward, Caroline, Author, Jamshidi, Yalda, Author, Jarvelin, Marjo-Riitta, Author, Jukema, J. Wouter, Author, Kaab, Stefan, Author, Kahonen, Mika, Author, Kanters, Jorgen K., Author, Kooperberg, Charles, Author, Lehtimaki, Terho, Author, Lima-Costa, Maria Fernanda, Author, Liu, Yongmei, Author, Loos, Ruth J. F., Author, Lubitz, Steven A., Author, Mook-Kanamori, Dennis O., Author, Morris, Andrew P., Author, O'Connell, Jeffrey R., Author, Olesen, Morten Salling, Author, Orini, Michele, Author, Padmanabhan, Sandosh, Author, Pattaro, Cristian, Author, Peters, Annette, Author, Psaty, Bruce M., Author, Rotter, Jerome, I, Author, Stricker, Bruno, Author, van der Harst, Pim, Author, van Duijn, Cornelia M., Author, Verweij, Niek, Author, Wilson, James F., Author, Arking, Dan E., Author, Ramirez, Julia, Author, Lambiase, Pier D., Author, Sotoodehnia, Nona, Author, Mifsud, Borbala, Author, Newton-Cheh, Christopher, Author, Munroe, Patricia B., Author
Source: Nature Communications. 13
Description: 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. 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.
File Description: electronic
Access URL: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-484905
https://doi.org/10.1038/s41467-022-32821-z
Database: SwePub
Description
ISSN:20411723
DOI:10.1038/s41467-022-32821-z