Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

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.

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.