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.