Echocardiography phenotyping in murine genetic reference population of BXD strains reveals significant eQTLs associated with cardiac function and morphology

Background: The genetic reference population of recombinant inbred BXD mice has been derived from crosses between C57BL/6J and DBA/2J strains. The DBA/2J parent exhibits cardiomyopathy phenotypes, while C57BL/6J has normal heart. BXD mice are sequenced for studying genetic interactions in cardiomyopathies. Objectives: The study aimed to assess cardiomyopathy traits in BXDs and investigate the quantitative genetic architecture of those traits. Methods: Echocardiography, blood pressure, and cardiomyocyte size parameters obtained from 44 strains of BXD family (N >5/sex) at 4-5 months of age were associated with heart transcriptomes and expression quantitative trait loci (eQTL) mapping was performed. Results: More than 2-fold variance in ejection fraction (EF%), fractional shortening (FS%), left ventricular volumes (LVVol), internal dimensions (LVID), mass (LVM), and posterior wall (LVPW) thickness was found among BXDs. In male BXDs, eQTL mapping identified Ndrg4 on chromosome 8 QTL to be positively correlated with LVVol and LVID and negatively associated with cardiomyocyte diameter. In female BXDs, significant eQTLs were found on chromosomes 7 and 3 to be associated with LVPW and EF% and FS%, respectively, and Josd2, Dap3 and Tmp3 were predicted as strong candidate genes. Conclusions: Our study found variable cardiovascular traits among BXD strains and identified multiple associated QTLs, suggesting an influence of genetic background on expression of echocardiographic and cardiomyocyte diameter traits. Increased LVVol and reduced EF% and FS% represented dilated cardiomyopathy, whereas increased LV mass and wall thickness indicated hypertrophic cardiomyopathy traits. The BXD family is ideal for identifying candidate genes, causal and modifier, that influence cardiovascular phenotypes.