Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Background Recent studies have shown an increasing prevalence of vascular risk factors in young adults with ischemic stroke ( IS ). However, the strength of the association between all vascular risk factors and early‐onset IS has not been fully established. Methods and Results We compared 961 patients with a first‐ever IS at 25 to 49 years to 1403 frequency‐matched stroke‐free controls from a population‐based cohort study ( FINRISK ). Assessed risk factors included an active malignancy, atrial fibrillation, cardiovascular disease, current smoking status, a family history of stroke, high low‐density lipoprotein cholesterol, high triglycerides, low high‐density lipoprotein cholesterol, hypertension, and type 1 and type 2 diabetes mellitus. We performed subgroup analyses based on age, sex, and IS etiology. In a fully adjusted multivariable logistic regression analysis, significant risk factors for IS consisted of atrial fibrillation (odds ratio [OR], 10.43; 95% confidence interval [ CI ], 2.33–46.77], cardiovascular disease (OR, 8.01; 95% CI , 3.09–20.78), type 1 diabetes mellitus (OR, 6.72; 95% CI , 3.15–14.33), type 2 diabetes mellitus (OR, 2.31; 95% CI , 1.35–3.95), low high‐density lipoprotein cholesterol (OR, 1.81; 95% CI , 1.37–2.40), current smoking status (OR, 1.81; 95% CI , 1.50–2.17), hypertension (OR, 1.43; 95% CI , 1.17–1.75), and a family history of stroke (OR, 1.37; 95% CI , 1.04–1.82). High low‐density lipoprotein cholesterol exhibited an inverse association with IS . In the subgroup analyses, the most consistent associations appeared for current smoking status and type 1 diabetes mellitus. Conclusions Our study establishes the associations between 11 vascular risk factors and early‐onset IS , among which atrial fibrillation, cardiovascular disease, and both type 1 and 2 diabetes mellitus in particular showed strong associations.

In patients with acute stroke, previous research has also shown sex to affect outcome after intravenous thrombolysis (IVT) treatment; although outcome was similar between men and women treated with placebo, outcome was better in women after IVT. 4 The biological explanation for this difference remains unclear.A possible explanation could be the difference in recanalization. Women have more cardioembolic strokes, with uniform fibrin-rich clots and therefore a higher affinity of alteplase, resulting in more frequent, faster, and complete recanalization. [5][6][7] Another suggested mechanism could be a difference in endogenous fibrinolysis because of differences in sex hormones between men and women. Estrogen has an indirect influence on the controlling of the fibrinolytic system, as well as a direct neuroprotective activity. [8][9][10][11] However, there are no convincing data to support these hypotheses.Background and Purpose-Women have a worse outcome after stroke compared with men, although in intravenous thrombolysis (IVT)-treated patients, women seem to benefit more. Besides sex differences, age has also a possible effect on functional outcome. The interaction of sex on the functional outcome in IVT-treated patients in relation to age remains complex. The purpose of this study was to compare outcome after IVT between women and men with regard to age in a large multicenter European cohort reflecting daily clinical practice of acute stroke care. Methods-Data were obtained from IVT registries of 12 European tertiary hospitals. The primary outcome was poor functional outcome, defined as a modified Rankin scale score of 3 to 6 at 3 months. We stratified outcome by age in decades. Safety measures were symptomatic intracranial hemorrhage and mortality at 3 months. Results-In this cohort, 9495 patients were treated with IVT, and 4170 (43.9%) were women with a mean age of 71.9 years.After adjustments for baseline differences, female sex remained associated with poor functional outcome (odds ratio, 1.15; 95% confidence interval, 1.02-1.31). There was no association between sex and functional outcome when data were stratified by age. Symptomatic intracranial hemorrhage rate was similar in both sexes (adjusted odds ratio, 0.93; 95% confidence interval, 0.73-1.19), whereas mortality was lower among women (adjusted odds ratio, 0.83; 95% confidence interval, 0.70-0.99). Conclusions-In this large cohort of IVT-treated patients, women more often had poor functional outcome compared with men. This difference was not dependent on age. (Stroke. 2017;48:699-703.