Abstract
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.
Original language | English |
---|---|
Article number | 5144 |
Number of pages | 18 |
Journal | Nature Communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Sept 2022 |
Access to Document
- 10.1038/s41467-022-32821-zLicence: CC BY
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In: Nature Communications, Vol. 13, No. 1, 5144, 01.09.2022.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
AU - Young, William J
AU - Lahrouchi, Najim
AU - Isaacs, Aaron
AU - Duong, ThuyVy
AU - Foco, Luisa
AU - Ahmed, Farah
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AU - Salman, Reem
AU - Noordam, Raymond
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AU - Haessler, Jeffrey
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AU - Weiss, Stefan
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AU - Moscati, Arden
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AU - Nursyifa, Casia
AU - Qian, Yong
AU - Richmond, Anne
AU - Roselli, Carolina
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AU - Tarazona-Santos, Eduardo
AU - Thériault, Sébastien
AU - van Duijvenboden, Stefan
AU - Warren, Helen R
AU - Yao, Jie
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AU - Aeschbacher, Stefanie
AU - Ahlberg, Gustav
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AU - Bis, Joshua C
AU - Boerwinkle, Eric
AU - Campbell, Archie
AU - Catamo, Eulalia
AU - Cocca, Massimiliano
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AU - De Luca, Antonio
AU - Ding, Jun
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AU - Ellinor, Patrick T
AU - Felix, Stephan B
AU - Froguel, Philippe
AU - Fuchsberger, Christian
AU - Gögele, Martin
AU - Graff, Claus
AU - Graff, Mariaelisa
AU - Guo, Xiuqing
AU - Hansen, Torben
AU - Heckbert, Susan R
AU - Huang, Paul L
AU - Huikuri, Heikki V
AU - Hutri-Kähönen, Nina
AU - Ikram, M Arfan
AU - Jackson, Rebecca D
AU - Junttila, Juhani
AU - Kavousi, Maryam
AU - Kors, Jan A
AU - Leal, Thiago P
AU - Lemaitre, Rozenn N
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AU - Mezzavilla, Massimo
AU - Mishra, Pashupati P
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AU - Mononen, Nina
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AU - Nauck, Matthias
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AU - Nikus, Kjell
AU - Pare, Guillaume
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AU - Pelliccione, Giulia
AU - Pittman, Alan
AU - Porteous, David J
AU - Pramstaller, Peter P
AU - Preuss, Michael H
AU - Raitakari, Olli T
AU - Reiner, Alexander P
AU - Ribeiro, Antonio Luiz P
AU - Rice, Kenneth M
AU - Risch, Lorenz
AU - Schlessinger, David
AU - Schotten, Ulrich
AU - Schurmann, Claudia
AU - Shen, Xia
AU - Shoemaker, M Benjamin
AU - Sinagra, Gianfranco
AU - Sinner, Moritz F
AU - Soliman, Elsayed Z
AU - Stoll, Monika
AU - Strauch, Konstantin
AU - Tarasov, Kirill
AU - Taylor, Kent D
AU - Tinker, Andrew
AU - Trompet, Stella
AU - Uitterlinden, André
AU - Völker, Uwe
AU - Völzke, Henry
AU - Waldenberger, Melanie
AU - Weng, Lu-Chen
AU - Whitsel, Eric A
AU - Wilson, James G
AU - Avery, Christy L
AU - Conen, David
AU - Correa, Adolfo
AU - Cucca, Francesco
AU - Dörr, Marcus
AU - Gharib, Sina A
AU - Girotto, Giorgia
AU - Grarup, Niels
AU - Hayward, Caroline
AU - Jamshidi, Yalda
AU - Järvelin, Marjo-Riitta
AU - Jukema, J Wouter
AU - Kääb, Stefan
AU - Kähönen, Mika
AU - Kanters, Jørgen K
AU - Kooperberg, Charles
AU - Lehtimäki, Terho
AU - Lima-Costa, Maria Fernanda
AU - Liu, Yongmei
AU - Loos, Ruth J F
AU - Lubitz, Steven A
AU - Mook-Kanamori, Dennis O
AU - Morris, Andrew P
AU - O'Connell, Jeffrey R
AU - Olesen, Morten Salling
AU - Orini, Michele
AU - Padmanabhan, Sandosh
AU - Pattaro, Cristian
AU - Peters, Annette
AU - Psaty, Bruce M
AU - Rotter, Jerome I
AU - Stricker, Bruno
AU - van der Harst, Pim
AU - van Duijn, Cornelia M
AU - Verweij, Niek
AU - Wilson, James F
AU - Arking, Dan E
AU - Ramirez, Julia
AU - Lambiase, Pier D
AU - Sotoodehnia, Nona
AU - Mifsud, Borbala
AU - Newton-Cheh, Christopher
AU - Munroe, Patricia B
N1 - © 2022. The Author(s).
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-32821-z
DO - 10.1038/s41467-022-32821-z
M3 - Article
C2 - 36050321
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5144
ER -