Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10⁻⁸). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.

心源性猝死占心血管疾病死亡人数的一半。心律失常的电生理学底物分析对于最佳风险分层至关重要。心电图上的 T 峰值到趋势 (Tpe) 间隔延长是心律失常风险增加的独立预测因素，而 Tpe 随心率的变化是更强的预测因素。然而，我们对支持这些危险因素的电生理机制的理解是有限的。我们对〜30,000个个体进行了静息Tpe和Tpe对运动和恢复的反应的全基因组关联研究（GWAS），然后在独立样本中进行复制（〜42,000个静息Tpe和〜22,000个Tpe对运动和恢复的反应），所有来自英国生物银行。分别正式复制了静息 Tpe 和运动 Tpe 反应的 15 个和 1 个单核苷酸变体。在完整的 GWAS 数据集中，另外 13 个静息 Tpe 位点、1 个 Tpe 对运动反应的位点和 1 个 Tpe 对运动反应的位点在全基因组范围内显着（p ≤ 5 × 10 ^-8 ）。性别特异性分析表明有七个额外的位点。总共，我们确定了 32 个静息 Tpe 位点，3 个 Tpe 对运动反应的位点，3 个 Tpe 对恢复调节心室复极以及心脏传导和收缩反应的位点。我们的研究结果揭示了静息 Tpe 以及 Tpe 对运动和恢复反应的遗传基础，揭示了心室兴奋性背后的合理候选基因和生物机制。