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

Young, William J; Lahrouchi, Najim; Isaacs, Aaron; Duong, ThuyVy; Foco, Luisa; Ahmed, Farah; Brody, Jennifer A; Salman, Reem; Noordam, Raymond; Benjamins, Jan-Walter; 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; ... (2022). Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. Nature communications, 13(1), p. 5144. Nature Publishing Group 10.1038/s41467-022-32821-z

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Risch, Lorenz

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Pubmed Import

Date Deposited:

05 Sep 2022 11:35

Last Modified:

06 Sep 2022 05:59

Publisher DOI:

10.1038/s41467-022-32821-z

PubMed ID:

36050321

BORIS DOI:

10.48350/172657

URI:

https://boris.unibe.ch/id/eprint/172657

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