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)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1–3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. 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 infarction6–9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Family History in Young Patients With Stroke

“…11 We confirm a maternal excess of stroke in female probands and extend this finding to a young stroke population. 2,6 Our data may underestimate the true effect of female-tofemale transmission.…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…The vascular finding is consistent with known co-morbidities and previously reported shared polygenic risk between migraine, stroke and cardiovascular diseases 70,71 . Furthermore, a recent GWA study of Cervical Artery Dissection (CeAD) identified a genome-wide significant association at exactly the same index SNP (rs9349379) as is associated to migraine in the PHACTR1 locus, suggesting the possibility of partially shared genetic components between migraine and CeAD 30 . These results suggest that vascular dysfunction and possibly also other smooth muscle dysfunction likely play roles in migraine pathogenesis.…”

“…Several of the genes have previous associations to vascular disease (PHACTR1, 29,30 TGFBR2, 31 [43][44][45] and coronary artery calcification 46 and rs11624776 at ITPK1 with thyroid hormone levels 47 ). Six of the loci harbor genes that are involved in nitric oxide signaling and oxidative stress (REST 48 , GJA1 49 , YAP1 50 , PRDM16 51 , LRP1 52 , and MRVI1 53 ).…”

Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis

“…RAPGEF2 has been found to be critical for murine embryonic hematopoiesis and to be differentially expressed in pulmonary arterial hypertension (47,48). PHACTR1 plays a role in the reorganization and regulation of the actin cytoskeleton and appears to influence important vascular functions (49,50). MCPH1 is a gene that encodes a DNA damage response protein (23).…”