A genetic approach to identify the common mechanisms of vascular disease

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Project Summary In my clinical training, I repeatedly saw the devastating effects of vascular disease on patients in the prime of their lives. Vascular diseases such as coronary artery disease (CAD), stroke, arterial dissection, and migraine headache combine to cause over half the death and disability in the United States1. To eradicate vascular disease it will be important to develop new treatments that target the arterial cells where the disease begins. The disease-causing pathways in these cells may be common to all vascular diseases, and their shared genetic risk can be a window into this pathophysiology. The loci associated with multiple vascular diseases have recently been identified through genome-wide association studies (GWAS). These loci represent new therapeutic targets, but their biological mechanisms remain largely unexplored. There are multiple challenges that exist for identifying these disease-causing biological mechanisms. First, each association often involves multiple variants. Second, most causal variants occur in non- coding regions, where the associated gene is unclear. Third, the relevant cell type is often critical for determining the function of a variant. I have identified new opportunities to address each of these challenges by integrating methods in GWAS analysis, single cell RNA-sequencing, and genome-editing of vascular cells. I utilized this approach to study the regulatory effect of the 6p24 locus on endothelin-1 expression, and aim to extend this unique combination of methods to the full set of pleiotropic vascular loci. This New Innovator Award application seeks to understand the intersecting mechanisms of multiple vascular diseases from the functional analysis of human genetic variation. The analytic pipeline I propose will prioritize loci with pleiotropic effects on three vascular diseases, and interrogate their combined effects on vascular cell function. I will establish an analytic pipeline to identify common vascular disease-associated loci and functionally characterize their biological effects. This will establish a new approach to the prioritization and functional characterization of vascular disease-causing variants, and identify new biological pathways for the treatment of multiple vascular diseases.