Ischemic stroke is the 4th leading cause of death in the U.S. and a major cause of disability. The etiology of stroke is multifactorial and poorly understood. Genetics is a potentially powerful tool for better understanding disease etiology as it can highlight biological mechanisms underlying disease and point the way to improved prevention and treatment. The NINDS-sponsored Stroke Genetics Network (SiGN) was formed in 2010 to identify common genetic variants associated with ischemic stroke and its subtypes using state-of-the-art stroke subtyping and the genome-wide association study approach in over 17,000 stroke cases from 25 sites. The initial meta-analysis, just completed, reveals several tantalizing results and a large number of additional analyses are planned by SiGN investigators. The goal of this application is to secure support for additional key analyses to be carried out on this unique resource and to make this resource available broadly to the international research community. Using already available genotype data, we will (1) Discover rare and low-frequency variants influencing stroke susceptibility by performing association analyses of low-frequency and exonic SNPs with ischemic stroke and its subtypes in 10,348 stroke cases and controls; (2) Identify the likely causal genes and variants at 7 established loci that have been robustly associated with ischemic stroke subtypes using integrative approaches to fine map these regions and define sets of credible causal variants; and (3) Contrast the nature of the genetic architecture among stroke subtypes between stroke and its risk factors using quantitative genetic analyses that partition SNPs across the genome into different bins, or categories, allowing us to test a variety of different hypotheses about the genetic architecture of stroke subtypes. A further goal of our proposal is to advance the pace of genetic discovery in stroke by making the SiGN resource (data and results) accessible to the stroke genetics community on a secure platform at the Broad Institute managed by the NINDS-funded Platform for Accelerating Genetic Discovery for Cerebrovascular Disease. As part of this effort we will create web-based look-up tools that allow investigators to query the meta- analysis results. In a very short period of time, SiGN has emerged as a unifying force in the stroke genetics field because of its inclusion of the leading stroke genetics groups internationally. The analyses and activities proposed in this application are key next steps that take advantage of this extraordinarily rich resource and set in place a mechanism for keeping this productive international consortium together and moving forward.