Fibromuscular dysplasia (FMD) is a non-atheroslcerotic, systemic arteriopathy with excess burden on women. FMD may have varying manifestations, including hypertension, stroke and myocardial infarction, among others, depending on the arterial beds involved by arterial stenosis, aneurysm, dissection or tortuosity. Thus, the clinical diagnosis of FMD encompasses a spectrum of arterial dysplasia phenotypes, and these may be either sporadic or familial. Our proposed studies will test the hypothesis that this spectrum of FMD implicates a limited number of genes and pathways, and a combined analysis of many cases, covering familial, sporadic, pediatric and adult cases, using both genetic and gene expression data, is the best way to uncover recurrently affected genes or convergent pathways. This hypothesis will be tested in three Specific Aims. Specific Aim 1: We will conduct gene discovery analyses of FMD in a large clinical resource of diverse demographic and phenotypic characteristics, in adult and pediatric cases of FMD, using both case-control approaches as well as family-based analyses. Specific Aim 2: We will conduct follow-up studies of genes associated with FMD, including studies of RNA expression in FMD and control arterial tissues and replication experiments in additional, independent samples. Specific Aim 3: Using functional laboratory approaches, we will test the cellular and arterial function of identified genes and variants relevant for arterial remodeling and dysplasia. The analyses and experiments proposed in these Specific Aims will allow us to systematically uncover causal DNA variants underlying FMD and to expand our knowledge of molecular defects driving arterial dysplasia.