Genetic Analyses of the Electrocardiographic QT Interval and Its Components Identify Additional Loci and Pathways

Citation

Young, William J.; Lahrouchi, Najim; Isaacs, Aaron J.; Duong, ThuyVy; Foco, Luisa; Ahmed, Farah; Brody, Jennifer A.; Salman, Reem; Noordam, Raymond; & Benjamins, Jan W., et al. (2022). Genetic Analyses of the Electrocardiographic QT Interval and Its Components Identify Additional Loci and Pathways. Nature Communications, 13(1), 5144. PMCID: PMC9436946

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.

URL

http://dx.doi.org/10.1038/s41467-022-32821-z

Reference Type

Journal Article

Year Published

2022

Journal Title

Nature Communications

Author(s)

Young, William J.
Lahrouchi, Najim
Isaacs, Aaron J.
Duong, ThuyVy
Foco, Luisa
Ahmed, Farah
Brody, Jennifer A.
Salman, Reem
Noordam, Raymond
Benjamins, Jan W.
Haessler, Jeffrey
Lyytikäinen, Leo-Pekka
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
Hines, Oliver
Isaksen, Jonas L.
Lin, Honghuang
Mei, Hao
Moscati, Arden
Müller-Nurasyid, Martina
Nursyifa, Casia
Qian, Yong
Richmond, Anne
Roselli, Carolina
Ryan, Kathleen A.
Tarazona-Santos, Eduardo
Thériault, Sébastien
van Duijvenboden, Stefan
Warren, Helen R.
Yao, Jie
Raza, Dania
Aeschbacher, Stefanie
Ahlberg, Gustav
Alonso, Alvaro
Andreasen, Laura
Bis, Joshua C.
Boerwinkle, Eric A.
Campbell, Archie
Catamo, Eulalia
Cocca, Massimiliano
Cutler, Michael J.
Darbar, Dawood
De Grandi, Alessandro
De Luca, Antonio
Ding, Jun
Ellervik, Christina
Ellinor, Patrick T.
Felix, Stephan B.
Froguel, Philippe
Fuchsberger, Christian
Gögele, Martin
Graff, Claus
Graff, Mariaelisa
Guo, Xiuqing
Hansen, Torben
Heckbert, Susan R.
Huang, Paul L.
Huikuri, Heikki V.
Hutri-Kähönen, Nina
Ikram, Arfan
Jackson, Rebecca D.
Junttila, Juhani
Kavousi, Maryam
Kors, Jan A.
Leal, Thiago P.
Lemaitre, Rozenn N.
Lin, Henry J.
Lind, Lars
Linneberg, Allan
Liu, Simin
MacFarlane, Peter W.
Mangino, Massimo
Meitinger, Thomas
Mezzavilla, Massimo
Mishra, Pashupati P.
Mitchell, Rebecca N.
Mononen, Nina
Montasser, May E.
Morrison, Alanna C.
Nauck, Matthias
Nauffal, Victor
Navarro, Pau
Nikus, Kjell
Pare, Guillaume
Patton, Kristen K.
Pelliccione, Giulia
Pittman, Alan
Porteous, David J.
Pramstaller, Peter P.
Preuss, Michael H.
Raitakari, Olli T.
Reiner, Alexander P.
Ribeiro, Antonio Luiz P.
Rice, Kenneth M.
Risch, Lorenz
Schlessinger, David
Schotten, Ulrich
Schurmann, Claudia
Shen, Xia
Shoemaker, Benjamin
Sinagra, Gianfranco
Sinner, Moritz F.
Soliman, Elsayed Z.
Stoll, Monika
Strauch, Konstantin
Tarasov, Kirill V.
Taylor, Kent D.
Tinker, Andrew
Trompet, Stella
Uitterlinden, André
Völker, Uwe
Völzke, Henry
Waldenberger, Melanie
Weng, Lu-Chen
Whitsel, Eric A.
Wilson, James G.
Avery, Christy L.
Conen, David
Correa, Adolfo
Cucca, Francesco
Dörr, Marcus
Gharib, Sina A
Girotto, Giorgia
Grarup, Niels
Hayward, Caroline
Jamshidi, Yalda
Järvelin, Marjo-Riitta
Jukema, J. Wouter
Kääb, Stefan
Kähönen, Mika
Kanters, Jørgen K.
Kooperberg, Charles
Lehtimäki, Terho
Lima-Costa, Maria Fernanda
Liu, Yongmei
Loos, Ruth J. F.
Lubitz, Steven A.
Mook-Kanamori, Dennis O.
Morris, Andrew P.
O'Connell, Jeffrey R.
Olesen, Morten S.
Orini, Michele
Padmanabhan, Sandosh
Pattaro, Cristian
Peters, Annette
Psaty, Bruce M.
Rotter, Jerome I.
Stricker, Bruno
van der Harst, Pim
van Duijn, Cornelia M.
Verweij, Niek
Wilson, James F.
Arking, Dan E.
Ramirez, Julia
Lambiase, Pier D.
Sotoodehnia, Nona
Mifsud, Borbala
Newton-Cheh, Christopher H.
Munroe, Patricia B.

Article Type

Regular

PMCID

PMC9436946

Data Set/Study

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Race/Ethnicity

European Ancestry
Hispanic Ancestry
African Ancestry
South Asian Ancestry
South-East Asian Ancestry

ORCiD

Avery - 0000-0002-1044-8162
Graff - 0000-0001-6380-1735