Genomic Structural Equation Modeling To Identify Shared And Distinct Genetic Drivers Of Cardiovascular Disease

Aneurysmal diseases of the aorta are among the most morbid cardiovascular diseases without effective medical therapies. Many genetic and environmental factors have been linked to thoracic and abdominal aortic aneurysmal disease; however, there is little data identifying shared and distinct genetic factors underlying aortic aneurysmal disease. In both diseases, degeneration of the medial smooth muscle layer leads to dilation of the vessel and predisposition to and rupture. Whether there are common and distinct genetic factors that function within the vasculature to predispose to aortic aneurysms is unknown. We utilized structural equation modeling to identify a common genetic signature associated with cardiovascular diseases and traits including: abdominal aortic aneurysms (AAA), thoracic aortic aneurysms (TAA), thoracic aortic diameter, peripheral arterial disease (PAD), and coronary artery disease (CAD) as a means to identify novel targets to study. We identified that AAA displays a positive genetic correlation with TAA as well as CAD and PAD. We then constructed a structural equation model that contained four novel factors: 1. Atherosclerotic factor, 2. Aneurysmal factor, 3. AAA-specific factor, 4. Aortic dimension factor. We identified that the atherosclerotic factor explained a large amount of genetic variance in CAD and PAD as well as a modest amount of variance in AAA. GWAS of the ‘atherosclerotic factor’ identified loci implicated in lipid homeostasis and inflammation. The ‘aneurysmal factor’ explained a large amount of genetic variance in TAA and aortic dimension as well as a modest amount in AAA. Notably GWAS for the ‘aneurysmal factor’ identified loci enriched in ECM components and smooth muscle contractile genes. Finally, we identified a factor explained the ‘residual’ genetic heritability underlying AAA. GWAS for this ‘residual factor’ identified a smaller number of hits enriched in matrix metalloprotease biology. Taken together, this study has highlighted the shared and distinct hereditability underlying aortic aneurysmal phenotypes and highlights a novel strategy for prioritizing loci for future study.