title: Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval.
abstract: 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.
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.|Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia.|Department of Genetics (GENIUROS), Escuela de Medicina y Ciencias de la salud, Universidad del Rosario, Bogotá, Colombia.
authors.forename: Claudia Tamar
authors.initials: CT
authors.lastname: Silva
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kors
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.|Center for Medical Systems Biology, Leiden, The Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.|Center for Medical Systems Biology, Leiden, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. aaron.isaacs@gmail.com.|Center for Medical Systems Biology, Leiden, The Netherlands. aaron.isaacs@gmail.com.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
mesh_terms: D000328:Adult; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable