Dissecting the Genetic Basis of the ECG as a Means of Understanding Mechanisms of Arrhythmia

Abstract

T he surface ECG records the electrical potential of the heart at the surface of the body as the electrical impulse travels throughout the heart with each heartbeat. The P wave represents depolarization of the atria, which spreads from the sinoatrial node toward the atrioventricular node and from the right to the left atrium. The PR interval reflects the time the electrical impulse takes to travel from the sinus node through the atrioventricular node. The QRS complex represents the rapid depolarization of the ventricles, and the T wave represents the repolarization of the ventricles. See Article by Christophersen et alThe ECG is one of the most accessible and valuable diagnostic tests. It informs about the presence of cardiac chamber enlargement/hypertrophy, conduction disturbance, arrhythmia, myocardial infarction/ischemia, and even provides indications for electrolyte imbalance or drug intoxication. Since about a decade, researchers have turned to the ECG as a tool to dissect the genetic basis of cardiac electrical function with the idea that the biological processes that underlie or impinge on the different parameters of the ECG are mediators (intermediate phenotypes, endophenotypes) of arrhythmia risk.1 This concept, which in itself is clearly intuitive, is supported by population-based studies that demonstrated that ECG parameters are associated with risk of arrhythmia or sudden cardiac death.2 The approach is furthermore rationalized by the fact that ECG parameters have been shown to have a heritable component (reviewed in reference 3 ). The first ECG parameter that was studied in this way by the genome-wide association study (GWAS) approach was the QT interval 1 ; in fact the QT interval was one of the first traits to be studied at the outset of the GWAS era 10 years ago. 4 Facilitated by the availability of large cohorts with ECG recordings and the ability to measure ECG parameters reproducibly in an automated fashion, GWAS has since been applied to several ECG parameters in increasingly larger cohorts of individuals primarily of European descent with >150 loci being identified as modulators of these traits. 5In the current issue of Circulation: Cardiovascular Genetics, Christophersen et al 6 report findings from a GWAS that they conducted on parameters related to the P wave in 44 456 individuals originating from 12 cohort studies. These parameters were namely P wave duration, so far understudied by GWAS, and P wave terminal force, studied by GWAS for the first time. Concordant with the intermediate phenotype paradigm, and the relationship between these parameters and atrial electrophysiology 7 and risk for atrial fibrillation (AF), 8 these investigators posited that elucidating genetic variants related to these parameters will help in understanding atrial electrophysiology and possibly uncover genetic determinants and mechanisms of AF. The authors further postulate that this may in turn allow identification of new therapeutic targets for AF. They report 15 loci that include loci previously identified fo...

Role of Genetic Variation in Transcriptional Regulatory Elements in Heart Rhythm

“…Quantitative electrocardiographic traits investigated in GWAS include QT interval and QRS duration, PR interval, heart rate, heart rate variability, and heart rate response to exercise and recovery (see https://www.ebi.ac.uk/gwas for an overview (accessed on 25 September 2023)) [54]. While these traits do not represent rhythm disorders, they are biomarkers for increased risks of developing an arrhythmia, such as AV block and atrial fibrillation (AF) (PR interval) and sinus node dysfunction ((variability in) heart rate; HR), and more generally have been associated with morbidity and mortality [55,56]. In addition, GWAS have uncovered a large number of SNPs associated with AF, made possible by the large number of registered AF cases [22,[57][58][59].…”

Genome-wide association studies of cardiac electrical phenotypes

“…Thus, ECG traits such as heart rate and conduction (PR-interval, QRS-duration) and repolarization parameters (QT-interval), are considered highly relevant ‘intermediate phenotypes’ of cardiac arrhythmia. 17 ECG parameters can be measured accurately and efficiently in large numbers of individuals and have been shown to display significant heritability (reviewed in Ref. 18 ) making them attractive traits to study by GWAS.…”