Project Summary Abstract Building on our 25-year track record in comprehensive genomic studies and addressing NHGRI's goal for this RFA, we propose to create, apply and test a powerful, reliable and general strategy for “comprehensive” identification of risk and protective variants that contribute significantly to any common disease of interest. Toward this end, we will: · Create a Common Disease Consortium (CDC) that brings together a collaborative network of investigators with deep clinical and genetic expertise and >1.1 million well-characterized samples (cases and controls) across diverse populations, including Europeans, African Americans, Hispanics and Asians. The CDC will undertake genetic studies under three major projects related to: (1) Five systemic diseases – early-onset coronary artery disease, type 2 diabetes, inflammatory bowel disease, atrial fibrillation, and stroke; (2) Three severe neurological disorders – autism, schizophrenia and epilepsy; and (3) Two countries with special advantages for genetic studies – Finland and Estonia. Through these three projects, the CDC will explore a range of study designs, population-genetic strategies, genetic architectures, and diverse populations. · Sequence 450,000 samples from the CDC, using the expertise of the Broad Institute's genomics platform to generate high quality data and to drive down sequencing costs. · Analyze the sequence data to elucidate the genetic basis of the diseases, by applying state- of-the-art methods from in our preliminary studies and developing new methods to increase power to detect association. · Create, disseminate and share data, tools, and resources, to enable the scientific community to access and analyze genetic studies from the CDC and other sources.