Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, affecting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity.

We aim at identifying genetic causes of FMD to better understand its mechanism and relation with other vasculopathies.

We report results from the first genome-wide association meta-analysis of six studies including 1962 FMD cases and 7100 controls. We integrated genetic association with arterial gene expression using transcriptome-wide association analysis. To identify FMD associated variants located in regulatory elements, we determined open chromatin regions in artery-derived primary cells using ATAC-Seq and estimated heritability and genetic correlation of FMD with other vascular traits and diseases using LD Score regression.

We found an estimate of SNP-based heritability compatible with a polygenic feature for FMD and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). We found that FMD associated variants were located in arterial-specific regulatory elements. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We found significant genetic overlap between FMD and blood pressure, although hypertension was not confounding the genetic association with FMD. We also report an important genetic overlap with migraine, intracranial aneurysm, coronary artery disease and LDL cholesterol.

We identified several loci related to vascular contraction, suggesting that altered vascular tonicity may play a role in the pathogenesis of FMD. We find that FMD is genetically close to several vascular diseases where vascular integrity is impaired.