Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects...

Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants. These analyses were conducted in a large, Dutch family-based cohort study, the Erasmus Rucphen Family study using variance component methods implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) software package. Heritability estimates ranged from 34% for QRS and Cornell voltage product to 49% for 12-lead sum. Trait-specific GWAS findings for each trait explained a fraction of their heritability (17% for QRS, 4% for QT, 2% for PR, 3% for Sokolow-Lyon index, and 4% for 12-lead sum). The inclusion of all ECG-associated single nucleotide polymorphisms explained an additional 6% of the heritability of PR. In conclusion, this study shows that, although GWAS explain a portion of ECG trait variability, a large amount of heritability remains to be explained. In addition, larger GWAS for PR are likely to detect loci already identified, particularly those observed for QRS and 12-lead sum.