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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.

The revolution in human genetics, catalyzed by the sequencing of the human genome in 2003 and the development of genome-wide genotyping technologies, has led to the identification of >2000 trait-associated genetic variants. Because most of these variants have individually small effects on disease risk, successful gene discovery efforts have required large sample sizes (involving thousands, tens, or hundreds of thousands of cases and controls) to achieve sufficient study power. Amassing such sample sizes has depended on international collaboration on a scale never seen before in human genetics or even in clinical research. Disease-specific consortia bringing together many individual sites and collaborators have now evolved for many major diseases. Each consortium has faced with ≥2 fundamental questions: how to assemble a study sample of sufficient size, homogeneity, and phenotypic quality and how to retain and analyze, sometimes repeatedly over several years, biological samples from enrolled subjects. The International Stroke Genetics Consortium (ISGC) has addressed these 2 challenges by taking into account the nature of the disease—stroke occurs suddenly with high case fatality (≤251 per 100 000; 5.9 million of 53 million reported deaths in 2010)1,2 and develops through multiple biological mechanisms. Because the stroke community consists of clinicians and investigators from across the world practicing in a range of environments with varied resources and constraints, the ISGC has developed processes that allow maximum flexibility while maintaining standardization, reliability, and quality. A central tenet of the consortium involves transparency and trust, without which large-scale collections and studies would not be possible. The growing collection of stroke samples created at the Massachusetts General Hospital under the auspices of the ISGC includes physical samples for ≈5000 cases and 4500 controls from >20 institutions in Europe, North America, South America, Australia, and Asia. …

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.