Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Abstract

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Figure 1

Regional association plot centered on rs9349379 (PHACTR1). Regional plot for associations in the region centered on rs9349379, drawn using LocusZoom software. All SNPs, on the basis of 1000 Genomes Project imputed results (dots), are plotted with their GWAS meta-analysis association P values against their genomic position. The color of the dots represents the LD between SNPs. The purple line represents the estimated recombination rates. Genes and exons are shown as dark blue arrows and vertical lines, respectively.