SummaryBackgroundVarious genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.MethodsWe meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.FindingsWe verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.InterpretationOur results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.FundingWellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome.

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.

on behalf of the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) GroupBackground-Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. Methods and Results-The study sample comprised 690 CEAD patients (mean age, 44.2Ϯ9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7Ϯ10.5 years; 39.9% women), and 1170 referents (45.9Ϯ8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index Ն30 kg/m 2 ) or overweightness (body mass index Ն25 kg/m 2 and Ͻ30 kg/m 2 ) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; PϽ0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; PϽ0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; Pϭ0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; PϽ0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. Conclusion-These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD. 4 -7 However, their specific impact on the occurrence of CEAD is poorly understood. Indeed, although the relationship of CEAD with vascular risk factors has been investigated in the past, studies were performed in small cohorts, 8 -19 and only 2 studies were specifically designed to assess this relationship. 16,19 A few studies reported a lower prevalence of vascular risk factors in CEAD patients compared with young patients with an IS of a cause other than CEAD (non-CEAD IS), 8 -10 whereas others did not observe any significant association. [11][12][13][14] Studies including referents are scarce [15][16][17]19 and yielded contradictory results: 1 study found no association 17 ; another observed a lower body mass index (BMI) 19 ; and 2 other studies found an increased prevalence of hypertension in CEAD patients compared with referents. 15,16 Clinical Perspective on p 1544The aim of the present analysis was to compare the prevalence of vascular ri...