This proposal will lead to identification of gene variants that increase the risk of developing cardiovascular disease. The underlying hypothesis is that systematic genetics conducted in model organisms enables the identification of disease-specific gene modules. This hypothesis will be tested in Phase I through the following Aims: (1) Create a database of phenotypes observed in systematic genetic screens conducted in yeast, worm, fly, zebrafish, and other model organisms. (2) Develop and apply data mining algorithms to identify modules of genes whose deletion or silencing phentoypes show similar patterns across model organisms. (3) Identify modules that are enriched for genes with known variants relevant to cardiovascular disease. Other genes in these modules will then be candidate genes for variants conferring cardiovascular disease risk or can be used to improve priors for whole-genome association tests. In Phase II, variants of candidate genes will be genotyped across a cardiovascular patient population with the goal of identifying genetic markers to assist in diagnosis and treatment of cardiovascular disease. If successful, this proposal will lead to genetic tests that will improve the clinical treatment of patients at risk for cardiovascular disease. The comparative systematic genetics platform developed will be broadly applicable to identifying gene modules relevant to other human diseases and will extend to systematic genetics data collected for a growing set of model organisms
