Abstract 468: Cross-species Comparison of Genetic Networks of Coronary Artery Disease

The genetic architecture of coronary artery disease (CAD), which represents the leading cause of death worldwide, has been investigated in both human populations and mouse models. However, whether the two species share similar genetic underpinnings has not been thoroughly evaluated. We hypothesize that a comprehensive data-driven integrative study leveraging multi-omics data resources will allow a tissue-specific, systems level assessment of the key similarities and differences in disease networks between mouse and man. To derive CAD genetic networks in mouse, we used genetic data from genome-wide association studies (GWAS) of atherosclerosis and functional genomics data of aorta and liver tissues from >100 strains profiled in an Atherosclerosis Hybrid Mouse Diversity Panel. To model human CAD genetic networks, we used human CAD GWAS from CARDIoGRAM+C4D, and functional genomics data from aorta and coronary arteries, and liver tissues from the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task and Genotype-Tissue Expression biobanks. We identified coexpression network modules and biological pathways that were significantly associated with genetic signals in each species. This tissue-specific analysis revealed that ~75 and ~80% of the pathways and networks were shared between species for vascular and liver tissues, respectively. The shared processes between species for both tissues included lipid and lipoprotein metabolism, MAPK, TCA, and notch signaling pathways; for vascular tissues the shared terms included biological oxidations, interferon, and cytokine signaling; for liver tissue, fatty acid metabolism, TGF-beta signaling, leukocyte transendothelial migration were shared between species. Viral myocarditis, platelet-derived growth factor signaling, fibrinolysis, and IL6/7 pathways were identified as human-specific, while insulin and nerve growth factor signaling were found to be mouse-specific. This cross-species tissue-specific integrative analysis provides insights into the convergent and divergent causal mechanisms underlying CAD between species and highlights the conditions in which mouse may or may not serve as a surrogate model for human CAD in disease mechanistic and preclinical studies.