Abstract P414: Systems Genetics Analysis Reveals Significant Eqtls Associated With Echocardiography Parameters In Genetic Reference Population Of Bxd Strains.

Abstract

Background: Causal and modifier genes, genetic background and environment underlie clinical heterogeneity in cardiomyopathy (CM). The BXD recombinant inbred (RI) family represents a murine genetic reference population (GRP) that are descendants from crosses between C57BL/6J (B6) and DBA/2J (D2) mice. The parental D2 mouse is a natural model of hypertrophic CM (HCM). The study aimed to dissect genetic architecture of cardiac traits in BXD GRP using systems genetics analysis. Methods: Echocardiography was performed in 88 strains of male (M) and female (F) BXDs (N>5/sex) at 4-5 months of age. Cardiac traits were then associated with heart transcriptome, and expression quantitative trait loci ( eQTL) mapping was performed. Results: More than 2-fold variance in ejection fraction (EF%), fractional shortening (FS%), left ventricular (LV) volumes at end-systole and end-diastole (Vol;s and Vol;d), internal dimensions (ID;s and ID;d), posterior wall (PW), and interventricular septum (IVS) thickness was found among BXDs. Traits seen in dilated CM (DCM) patients such as reduced EF%, FS%, and LVPW and increased Vol;s and ID;s are found in BXD78 (M, F), BXD32, 111, and 68 (F) strains. Strains D2, BXD90 and 155 (M, F), BXD44 and 65 (M), and BXD113, 16, 77 (F) had significantly greater LV mass, LVPW and IVS thickness compared to sex-matched controls, suggestive for traits seen in HCM patients. A 6.4 Mb QTL (peak LRS=18.50) was identified on chromosome (Chr) 8 to be significantly associated with ID;s, ID;d, Vol;s and Vol;d among male BXDs. eQTL mapping for each of 131 genes on Chr8 QTL identified 6 genes ( Coq9 , Ndrg4 , Crnde, Irx3, Rpgrip1l, and Rbl2 ) being cis -regulated and Ndrg, Slc6a2 and Ces1d being significantly (p < 0.05) correlated with LV volumes. In female BXDs, a significant QTL on Chr7 (40.2 Mb) with 9 genes that significantly correlated with LVPW;d was identified. A suggestive 92.6 Mb QTL on Chr3 with Snapin , Tpm3 , and Wars2 correlated with EF% and FS% (p < 0.05). Conclusions: Our study found cardiomyopathy-associated traits are segregated among BXD family and these traits vary among BXD lines. Multiple associated QTLs demonstrate that the BXD family is suitable to map gene variants and identify genetic factors and modifiers that influence cardiomyopathy phenotypes.