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.

心脏性猝死占所有心血管疾病死亡的一半。分析心律失常的电生理底物对于最佳风险分层至关重要。心电图上延长的 T-peak-to-Tend (Tpe) 间期是心律失常风险增加的独立预测因子，而 Tpe 随心率的变化甚至是更强的预测因子。然而，我们对支持这些风险因素的电生理机制的理解是有限的。我们针对约 30,000 个人的静息 Tpe 和 Tpe 对运动和恢复的反应进行了全基因组关联研究 (GWAS)，然后在独立样本中进行复制（约 42,000 个用于静息 Tpe，约 22,000 个用于 Tpe 对运动和恢复的反应），所有来自英国生物银行。分别用于静息 Tpe 和 Tpe 对运动的反应的十五个和一个单核苷酸变体被正式复制。在完整数据集 GWAS 中，另外 13 个位点用于静息 Tpe、1 个用于 Tpe 对运动的反应和 1 个用于 Tpe 对运动的反应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。总的来说，我们确定了 32 个用于静息 Tpe 的位点，3 个用于 Tpe 对运动的反应，3 个用于 Tpe 对恢复调节心室复极化以及心脏传导和收缩的反应。我们的研究结果揭示了静息 Tpe 和 Tpe 对运动和恢复的反应的遗传基础，揭示了可能的候选基因和心室兴奋性的生物学机制。