M16 - International Stroke Genetics Consortium

Investigator Names and Contact Information

Sylvia Smoller (Sylvia.Smoller@einsteinmed.edu)

Introduction/Intent

Ischemic stroke is a complex genetic disorder. Limited progress has been made to unravel the genetics of ischemic stroke since, until recently, the field has been hampered by inadequate cross-study collaborations that have resulted in multiple studies of small sample size with unsophisticated phenotyping. This application for a genome-wide association study (GWAS), submitted in response to NINDS Funding Opportunity Announcement RFA-NS-09-002, builds on the innovative collaborations established through the International Stroke Genetics Consortium (ISGC). It will greatly advance the field of ischemic stroke genetics by establishing a large 10-study collaboration of unique scale that will bring together the world’s leading clinician-scientists in stroke genetics to generate well-powered genetic investigations with careful, uniform phenotyping.

The successful identification of common gene variants and novel pathways underlying risk of ischemic stroke has the potential to transform our understanding of the pathophysiology, treatment, and prevention of the third leading cause of death worldwide. Our study will thoroughly test the hypothesis that common variants play a major role in stroke, setting the stage for the future genetic study of this disease. The team’s proven track record of collaboration and cutting-edge research in the neuroimaging and epidemiology of stroke as well as in human genetic variation, along with our aggressive data release policy, will ensure the substantial investment in phenotyping and genotyping results in the widest possible benefit for present and future patients.

Our 3 specific aims and their components are detailed below:

1.1. Assemble ischemic stroke phenotypic data and high quality DNA samples from 10 stroke studies. Participating studies in the NINDS International Stroke Genetics Consortium Study (NINDS ISGC Study): Ischemic Stroke Genetics Study; Siblings with Ischemic Stroke Study; Greater Cincinnati/Northern Kentucky Stroke Study; Genes Affecting Stroke Risk and Outcome Study/Bugher Network Study; Northern Manhattan Study; Baltimore-Washington Young Stroke Study; Heart and Vascular Health Stroke Study; Nurses Health Study; Reasons for Geographic and Racial Differences in Stroke; Women’s Health Initiative).

This collaboration has access to 7,033 cases of ischemic stroke and 23,411 study-specific controls.

• Harmonize phenotypic data, including stroke subtypes;
• Assure appropriately collected and quantified DNA for high throughput genotyping;
• Prepare sample manifests and organize transfer of samples from individual study sites to the genotyping center;
• Prepare phenotype data and supporting documentation for submission to dbGaP; and
• Coordinate with the Genotyping Center for new genotyping of samples in an estimated 4,420 cases and 3,277 controls.

1.2. Test for associations with ischemic stroke and its subtypes in the NINDS ISGC Study.

• Impute genotypes to establish formal baseline genetic data to enhance information content in study-specific samples and to permit meta analyses;
• Perform study study-specific analyses of ischemic stroke and its subtypes;
• Combine study-specific results for a meta-analysis of ischemic stroke and its subtypes; and
• Perform secondary meta-analyses of stroke subtypes and sub-populations (e.g., ethnic group, gender, age of onset).

1.3. Replicate and extend associations detected in Aim 1.2 above by taking advantage of other genome-wide association studies conducted by other members of the ISGC.

• Conduct an in silico replication of associated SNPs in genome-wide datasets of the Wellcome Trust Case-Control Consortium, the Australian National Research Council Study, and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE); and
• Perform combined meta-analysis of the NINDS ISGC Study with the Wellcome Trust, Australian, and CHARGE studies to identify additional stroke-associated SNPs.

Case Selection for M16 - International Stroke Genetics Consortium

The 844 cases for this study were selected from the 972 ischemic cases selected for AS126 - Hormones and Biomarkers Predicting Stroke in Women who were eligible for dbGaP. The 972 ischemic cases included cases:

• as of Aug. 31, 2004,
• with no prior history of MI or stroke, and
• with adequate available EDTA and citrate for assays in AS126.