Genetic mapping of electrocardiographic parameters in BXD strains reveals Chromosome 3 loci to be associated with cardiac repolarization abnormalities

Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 mo of age (<i>n</i> ≥ 5 mice/sex/strain). ECG and arrhythmia traits were associated with echocardiography, blood pressure, genome, and heart transcriptome data followed by expression QTL mapping. A significant variability in ECG parameters and arrhythmias was recorded among BXDs. Among male BXDs, QRS duration was significantly associated with increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening, whereas premature ventricular contractions (PVCs) were correlated with LVID, left ventricular (LV) volumes, and pulmonary vein peak pressure. In female BXDs, PVCs and premature atrial contractions (PACs) were significantly related with right ventricular ID and cardiac output. One significant QTL associated with QTc and JT durations was identified on Chromosome (Chr) 3 in male BXDs, whereas Chr 9 locus was suggestive for association with QTc and QT intervals in female mice. <i>Gon4l</i> was predicted as a strong candidate gene associated with repolarization abnormalities including short or long QT syndromes in humans. Study results suggested an influence of genetic background on expression of ECG parameters and arrhythmias based on significant variations of those traits between mouse strains of the BXD family. We conclude that murine BXD family can serve as a valuable reference for systems biology and comparative predictions of arrhythmia disorders.<b>NEW & NOTEWORTHY</b> Our study identified significant variances in ECG phenotypes and arrhythmias segregation in BXD mice. A significant quantitative trait locus (QTL) on Chromosome (Chr) 3 in the mouse genome was associated with increased QTc and JT intervals in male BXD mice. A suggestive QTL on Chr 9 associated with QT and QTc intervals was determined in female BXD mice. We identified a strong candidate gene, <i>Gon4l</i>, that may underlie cardiac repolarization abnormalities such as long and short QT syndromes.