Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval

Abstract

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 3 10 À8 ). 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.

Interaction Between ECG and Genetic Markers of Coronary Artery Disease

“…The integration of ECG and genetic markers into a combined score could also be potentially used to study the evolution and the mechanisms of CAD risk (genotypephenotype interactions) [12]. In addition, recent publications on the genetics of ECG markers of cardiovascular risk have reported GRSs for these ECG risk markers [5,9,13,14]. However, the role that these GRSs play when integrated into combined risk scores with independent clinical and non-invasive cardiac markers remains to be elucidated.…”

Analysing electrocardiographic traits and predicting cardiac risk in UK biobank

“…From these, 12 were also associated with resting QT, 2 with resting heart rate, 5 with QRS complex and 3 with the PR interval, indicating shared genetic architecture among ECG traits. 6 However, 10 loci were specific to the Tpe interval (i.e. not previously reported for any other ECG trait), and 8 had plausible candidate genes ( PPP1R3B/MFHAS1 , PYGB , KCNJ4 , GATA4 , RUFY1 , SERTAD2 , GPR1/ZDBF2 and HEY2) .…”

“…Raw digital ECG recordings enabled detailed analysis of exercise related biomarkers. We focused on subjects without a history of known cardiovascular disease as this affects heart rate., Automatic quantification of the ECG indices was performed as follows: 4 – 7 Computation of signal-averaged ECG waveforms : Signal averaging is a standard and effective technique to reduce noise and artefacts from ECG recordings. ECG waveforms of successive heartbeats within short intervals of interest (e.g.…”

“…The T-peak-to-T-end (Tpe) interval measures the distance between the peak and the end of the T-wave, and is heritable 6 ( Figure 2 ). In the largest study to date, we identified 28 loci and 4 male-specific loci contributing to the Tpe interval.…”

Genetic Architecture of Quantitative Cardiovascular Traits: Blood Pressure, ECG and Imaging Phenotypes

“…A large genome-wide association meta-analysis (n ~ 103,331) of QT interval yielded a total of 35 genome-wide significant loci which harbour not only known genes implicated in LQTS, but novel genes such as ATP2A2, PLN, PRKCA, SRL and SLC8A1 that modulate the calcium signalling pathway (18). A more refined assessment of repolarisation, namely T-peak-to-T-end-interval (Tpe), has been investigated in a GWAS which identified 32 loci comprising genes involved in cellular processes of ventricular repolarisation (19). More recently, several studies have looked into exercise ECG measurements which are known to be prognostically important.…”