Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9 (HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes.

Objective Prior studies investigating the association between APOE alleles ε2 / ε4 and risk of Intracerebral Hemorrhage (ICH) have been inconsistent, limited to small sample sizes and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2,189 ICH cases and 4,041 controls from seven cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases and 357 controls) had available genome-wide data to adjust for population stratification. Results ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (Odds Ratio (OR) = 1.82, 95% Confidence Interval (CI) 1.50 – 2.23, p = 6.6 × 10−10 and OR = 2.20, 95%CI 1.85 – 2.63, p = 2.4 × 10−11 respectively). Restriction of analysis to definite / probable CAA ICH uncovered a stronger effect. ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI 1.08 – 1.36, p = 2.6 × 10−4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.

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SUMMARY Background APOE alleles ε2/ε4 increase risk of intracerebral hemorrhage (ICH) in the lobar regions, presumably through their influence on risk of cerebral amyloid angiopathy. We investigated whether these variants also associate with ICH severity, specifically larger ICH volume at presentation. Methods We initially investigated the association of ε2/ε4 with ICH volume and outcome in a Discovery sample of 865 individuals of European ancestry. Replication was completed in two samples, comprising 946 Europeans (Replication I) and 214 African-Americans (Replication II) respectively. Admission ICH volume was quantified on CT scan. Poor functional outcome (modified Rankin Scale: 3 – 6) and mortality were assessed at 90 days. Findings Among patients with lobar ICH, APOE ε2 was associated with larger ICH volume: each allele copy increased hematoma size by 5·3 cc (95% CI 4·1 – 6·2 cc, p = 0.004), with replication in Europeans (p = 0·008) and African Americans (p = 0·016). Consistent with this, ε2 was associated with both mortality (OR = 1·50, 1·23 – 1·82, p = 2·45 × 10−5) and poor functional outcome (OR = 1·52, 1·25 – 1·85, p = 1·74 × 10−5). We were not able to replicate published associations between ε4 and overall ICH mortality in a meta-analysis of all available data (n = 2202 ICH cases, OR = 1·08, 95% CI: 0·86 – 1·36, p = 0·52). Interpretation In lobar ICH, APOE ε2 is associated with larger ICH volume at presentation, and hence increased mortality and disability. These findings suggest a role for the vasculopathic changes associated with the ε2 allele in influencing the severity and clinical course of lobar ICH. Funding This study was funded by NIH-NINDS, the American Heart Association, government agencies in Spain, Poland and Austria, academic institutions in Sweden and Austria, and philanthropic organizations.

Background White matter hyperintensity (WMH), or leukoaraiosis, is a radiological finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relationship to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small vessel disease such as intracerebral hemorrhage (ICH) are associated with low levels of cholesterol. We sought to determine the relationship between hyperlipidemia (HL) and WMH severity in patients with acute ischemic stroke (AIS). Methods We analyzed two independent hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semi-automated volumetric image analysis and a semi-quantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relationship between WMH severity and study variables. Results A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (p<0.001) in both cohorts. In the multivariable analysis, after controlling for age, gender, and those significant risk factors in the univariate and age-adjusted analyses, patients with a history of HL had less severe WMH in both cohorts (p<0.01). Conclusions Results from two independent cohorts demonstrate that AIS patients with a history of HL have less severe WMH at the time of stroke. These data support the hypothesis that HL may play a relatively protective role on cerebral small vessel disease.

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Objective: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences ␤-amyloid (A␤) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular A␤ deposition. Methods:We performed a case-control genetic association study of 89 individuals with CAArelated ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICHfree control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. Results GLOSSARYA␤ ϭ ␤-amyloid; AD ϭ Alzheimer disease; BA ϭ Brodmann area; CAA ϭ cerebral amyloid angiopathy; CAA-ICH ϭ cerebral amyloid angiopathy-related intracerebral hemorrhage; CI ϭ confidence interval; GOCHA ϭ Genetics Of Cerebral Hemorrhage on Anticoagulation; GWAS ϭ genome-wide association studies; HR ϭ hazard ratio; HTN-ICH ϭ hypertension-related intracerebral hemorrhage; ICH ϭ intracerebral hemorrhage; MAF ϭ minor allele frequency; MAP ϭ Rush Memory and Aging Project; OR ϭ odds ratio; PCA ϭ principal component analysis; ROS ϭ Religious Order Study; SNP ϭ single nucleotide polymorphism.Cerebral amyloid angiopathy (CAA) is characterized by ␤-amyloid (A␤) peptide deposition in the walls of arterial vessels of the cerebral cortex and cerebellum. 1,2 Like the amyloid plaques in Alzheimer disease (AD), vascular amyloid is composed of a proteolytic fragment (A␤) of the ␤-amyloid precursor protein. A␤ deposition is responsible for a variety of clinical consequences, including acute intracerebral hemorrhage (ICH).3-6 CAA-related ICH 7 accounts for between 15% and 40% of all nontraumatic ICH in elderly individuals and is associated with mortality rates of

Objectives: Intracerebral hemorrhage (ICH) is a highly lethal disease of the elderly. Use of statins is increasingly widespread among the elderly, and therefore common in patients who develop ICH. Accumulating data suggests that statins have neuroprotective effects, but their association with ICH outcome has been inconsistent. We therefore performed a meta-analysis of all available evidence, including unpublished data from our own institution, to determine whether statin exposure is protective for patients who develop ICH. Methods:In our prospectively ascertained cohort, we compared 90-day functional outcome in 238 pre-ICH statin cases and 461 statin-free ICH cases. We then meta-analyzed results from our cohort along with previously published studies using a random effects model, for a total of 698 ICH statin cases and 1,823 non-statin-exposed subjects. Conclusion: Antecedent use of statins prior to ICH is associated with favorable outcome and reduced mortality after ICH. This phenomenon appears to be a class effect of statins. Further studies are required to clarify the biological mechanisms underlying these observations. Results Neurology® 2011;76:1581-1588 GLOSSARY CI ϭ confidence interval; GCS ϭ Glasgow Coma Scale score; ICH ϭ intracerebral hemorrhage; LDL ϭ low-density lipoprotein; MGH ϭ Massachusetts General Hospital; mRS ϭ modified Rankin Scale; OR ϭ odds ratio.Intracerebral hemorrhage (ICH) accounts for 15% of all acute strokes, with societal and public health ramifications largely determined by the associated prognosis. 1 Despite substantial advances in the field of neurocritical care, more than half of patients with ICH face the prospect of death or severe disability.2 New research directions are therefore crucially needed in order to understand the complex pathophysiology of ICH outcome and recovery and exploit this understanding to benefit patients. 3Several studies investigating animal models of ICH suggest that statins exert a beneficial effect on functional recovery. [4][5][6] These findings could be explained by the effect of statins on lipid metabolism, or by other effects including neuroprotection and stimulation of neurogenesis and synaptogenesis. 7,8 Evidence from observational studies in patients, however, is conflicting, with some groups