William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK.
Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK.
Nat Commun. 2022 Sep 1;13(1):5144. doi: 10.1038/s41467-022-32821-z.
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.
QT 间期是一种心电图测量值，代表心室去极化和复极的总和，分别由 QRS 持续时间和 JT 间期估计。QT 间期异常与潜在致命性室性心律失常有关。我们使用全基因组多祖先分析（>25 万个体），分别鉴定出 QT、JT 和 QRS 的 177、156 和 121 个独立位点，包括一个男性特异性 X 染色体位点。使用基于基因的罕见变异方法，我们鉴定出与孟德尔疾病基因的关联。在 QT 和 JT 的既定途径中观察到富集，并且在胰岛素受体信号传导和心脏能量代谢中指出了以前未报告的基因。相比之下，对于 QRS，细胞生长和细胞外基质相互作用的结缔组织成分和过程显著富集。我们证明了多基因风险评分与心房颤动、传导疾病和心源性猝死的关联。对可成药性基因的优先级排序突出了心律失常的潜在治疗靶点。总之，这些结果大大提高了我们对心室去极化和复极遗传结构的理解。
