Abstract 384: Integration of Aorta Network Models from Mouse Ath-HMDP with Human GWAS Reveals Novel Mechanisms of Coronary Artery Disease

Abstract

Coronary artery disease (CAD) remains one of leading causes of death worldwide. Although the genetic heritability of CAD has been estimated to be 40 to 60%, only ~10% can be explained by the genetic loci uncovered from recent large-scale human GWAS. To elucidate the missing mechanisms, we leveraged aorta transcriptome data from 372 mice profiled in an Atherosclerosis Hybrid Mouse Diversity Panel (ath-HMDP), human CAD GWAS from CARDIoGRAM+C4D, and human expression quantitative loci (eQTL) from the Genotype-Tissue Expression (GTEx) and the Cardiogenics transcriptomic studies. We first constructed aorta coexpression networks based on the ath-HMDP transcriptome data using MEGENA (Multiscale Embedded Gene Co-expression Network Analysis) and WGCNA (Weighted Gene Coexpression Network Analysis) to define coexpression modules with various levels of coherency and compactness. The coexpression modules from MEGENA and WGCNA were then correlated with the aortic lesion trait measured in ath-HMDP to reveal 29 coexpression modules demonstrating significant correlations with aortic lesions (p < 1e-3). We further integrated these aortic lesion-correlated modules with eQTLs from aortic and coronary arteries examined in the GTEx study and monocyte and macrophage eQTLs from Cardiogenics to map module genes to functional SNPs that likely affect the expression levels of these genes. When further incorporating the CARDIoGRAM+C4D CAD GWAS, 13 lesion-correlated modules in mouse ath-HMDP were enriched for functional SNPs demonstrating stronger association with CAD in humans. These modules were over-represented with genes in multiple biological pathways, including both known CAD processes (e.g., lipid & lipoprotein metabolisms, fatty acid triacylglycerol & ketone body metabolism, TCA cycle, vascular smooth muscle contraction, antigen processing, focal adhesion) and novel pathways (e.g., adipocytokine signaling, type I & II diabetes mellitus, neurotrophic factor signaling, lysosome). In conclusion, this cross-species integrative analysis that takes advantage of aorta profiling from a well-controlled mouse atherosclerosis study in conjunction with human genomics provides insights into the aorta-related mechanisms underlying CAD.