Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 09 2022
01 09 2022
Historique:
received:
19
11
2021
accepted:
17
08
2022
entrez:
1
9
2022
pubmed:
2
9
2022
medline:
9
9
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36050321
doi: 10.1038/s41467-022-32821-z
pii: 10.1038/s41467-022-32821-z
pmc: PMC9436946
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5144Subventions
Organisme : Medical Research Council
ID : MR/N025083/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL139731
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007604
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL148521
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142825
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107786
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL127704
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110113
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG068221
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128914
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141989
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143070
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM115428
Pays : United States
Organisme : Medical Research Council
ID : MR/R017468/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : T32 HL139439
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142302
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138737
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL105780
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007416
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG051129
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124097
Pays : United States
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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