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.

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

Background and Purpose Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOE loci and at 12% (SE, 4%) for APOE. Conclusions Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.