Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected.

We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array.

We followed up 13 loci (p<10⁻⁴) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, (p = 7.4×10⁻¹⁰, n all cases = 1154, n all controls = 3895).

The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (p=0.0009), increased intima media thickness (p=0.001) and wall cross-sectional area (p=0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients (n=20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients (p=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (p=0.003) indicating impaired development of vasculature.

Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.