The genetic makeup of the electrocardiogram

Abstract Since its original description in 1893 by Willem van Einthoven, the electrocardiogram (ECG) has been instrumental in the recognition of a wide array of cardiac disorders1,2. Although many electrocardiographic patterns have been well described, the underlying biology is incompletely understood. Genetic associations of particular features of the ECG have been identified by genome wide studies. This snapshot approach only provides fragmented information of the underlying genetic makeup of the ECG. Here, we follow the effecs of individual genetic variants through the complete cardiac cycle the ECG represents. We found that genetic variants have unique morphological signatures not identfied by previous analyses. By exploiting identified abberations of these morphological signatures, we show that novel genetic loci can be identified for cardiac disorders. Our results demonstrate how an integrated approach to analyse high-dimensional data can further our understanding of the ECG, adding to the earlier undertaken snapshot analyses of individual ECG components. We anticipate that our comprehensive resource will fuel in silico explorations of the biological mechanisms underlying cardiac traits and disorders represented on the ECG. For example, known disease causing variants can be used to identify novel morphological ECG signatures, which in turn can be utilized to prioritize genetic variants or genes for functional validation. Furthermore, the ECG plays a major role in the development of drugs, a genetic assessment of the entire ECG can drive such developments.