Summary Introduction The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading approach to the identification of novel biological pathways for human disease. To date, GWAS have had been limited by relatively small sample sizes and yielded relatively few loci associated with ischemic stroke The National Institute of Neurological Disorders Stroke Genetics Network (NINDS-SiGN) is an international consortium that has taken a systematic approach to phenotyping and produced the largest ischemic stroke GWAS to date. Methods In order to identify genetic loci associated with ischemic stroke, we performed a two-stage genome-wide association study. The first stage consisted of 16,851 cases with state-of-the-art phenotyping and 32,473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtyped by centrally trained and certified investigators using the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identify samples genotyped on (nearly) identical arrays and of similar genetic ancestral background. Data was cleaned and imputed using dense imputation reference panels generated from whole-genome sequence data. Genome-wide testing was performed within each stratum for each available phenotype, and summary level results were combined using inverse variance-weighted fixed effects meta-analysis. The second stage consisted of in silico look-ups of 1,372 SNPs in 20,941 cases and 364,736 stroke-free controls, with cases previously subtyped using the TOAST classification system according to local standards. The two stages were then jointly analyzed in a final meta-analysis. Findings We identified a novel locus at 1p13.2 near TSPAN2 associated with large artery atherosclerosis (LAA)-related stroke (stage I OR for the G allele at rs12122341 = 1·21, p = 4.50 × 10−8; stage II OR = 1·19, p = 1·30 × 10−9). We also confirmed four loci robustly associated with ischemic stroke and reported in prior studies, including PITX2 and ZFHX3 for cardioembolic stroke, and HDAC9 for LAA stroke. The 12q24 locus near ALDH2, originally associated with all ischemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke. Other loci, including NINJ2, were not confirmed. Interpretation Our results identify a novel LAA-stroke susceptibility gene and now indicate that all loci implicated by GWAS to date are subtype specific. Follow-up studies will be necessary to determine whether the locus near TSPAN2 yields a novel therapeutic approach to stroke prevention. Given the subtype-specificity of these associations, the rich phenotyping available in SiGN is likely to prove vital for further genetic discovery in ischemic stroke. Funding National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH).

Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered

Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). 8 The database covers 600 consecutively recruited patients diagnosed with ischemic stroke before the age of 70 within 4 stroke units in western Sweden between 1998 and 2003 and 600 ageand sex-matched controls who were selected randomly from a group of participants in a population-based health survey. For both stroke cases and controls, recurrent stroke and deaths between SAHLSIS baseline and follow-up have been identified using the Swedish Cause of Death Register and the National Patient Register.9 For the 7-year follow-up,Background and Purpose-The consequences for the family of stroke survivor are generally studied in a short-term perspective. The aim of this study was to assess long-term aspects of health-related quality of life among spouses of stroke survivors. Methods-Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The health-related quality of life of spouses was assessed by the Short Form-36, and the characteristics of stroke survivors were assessed using the National Institutes of Health Stroke Scale, the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, the Barthel Index, and the modified Rankin Scale. Results-Dyads of 248 stroke survivors aged <70 at stroke onset and 245 dyads of matched controls were included. Spouses of stroke survivors and spouses of controls had a median age of 64 and 65, respectively; proportion of men was 35% and 34%, respectively. The spouses of stroke survivors reported lower scores in all the mental domains (P=0.045; P<0.001), as well as in the domains of general health (P=0.013) and physical role (P=0.006), compared with the spouses of controls. Predictors of poor physical health of the spouses were their own age and the level of global disability of the stroke survivor. Predictors of poor mental health of the spouses were depressive symptoms, cognitive impairment, and global disability among the stroke survivors. Conclusions-The

Introduction: Poststroke epilepsy (PSE) is the most common form of acquired epilepsy after middle age. The primary aim of this study was to study the impact of PSE on prognosis. A secondary aim was to validate recent findings from smaller studies on the risk of developing PSE on a nationwide scale. Patients and methods: We performed a nationwide cohort study based on comprehensive national registries and included patients without a prior epilepsy diagnosis surviving more than 2 months after stroke, identified by the Swedish Stroke Register (Riksstroke) and linked to the National Patient Register and Cause of Death Register. Cox proportional timeupdated hazard model was used to assess the risk of death, with or without multivariable adjustment for possible confounders, and multiple Cox regression was used to examine associations between PSE and clinical characteristics. Results: In 106,455 patients, PSE (defined as a seizure diagnosis more than 7 days after stroke) was detected in 7.3%, with lower cumulative incidence after ischemic stroke (6.4%) than after intracerebral haemorrhage (12.4%). Stroke severity, intracerebral haemorrhage and young age were associated with a risk of PSE. The risk of death was increased in patients with PSE (hazard ratio: 1.68, 95% confidence interval: 1.25-1.53). Also with adjustments for age, comorbidities and stroke severity, an increased risk of death associated with PSE remained. Discussion: Studies are needed on potential causes of increased mortality in PSE, such as a direct seizure-related mortality, less ambitious secondary stroke prophylaxis or rehabilitation, or impact of antiepileptic drugs on cardiovascular risk.