There is a large need for revitalization of the research on coronary heart disease (CHD) including: a) improved risk prediction and more adequate individually-tailored treatment; and b) new targets for drug development based on pathways previously unknown to be involved in CHD pathophysiology.The overall goal of this proposal is to improve prevention and treatment of CHD through better understanding of the biology underlying disease development, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development.The specific aims are to:1) Establish and characterize causal genes in known CHD loci (gene regions) through: a) resequencing of known CHD loci; b) expression profiling in liver, arteries, myocardium and skeletal muscle; c) high-throughput protein profiling; and d) experimental follow-up in zebrafish (Danio rerio) models.2) Discover new proteins, metabolites and pathways involved in CHD pathophysiology using global proteomic and metabolomic profiling to provide new biomarkers and drug targets.We will integrate genomic, transcriptomic, metabolomic and proteomic data from five longitudinal, population-based cohort studies with detailed phenotyping and one study with tissue collections for expression studies. The cohort studies include 36,907 individuals; there are 3,093 prevalent CHD cases at baseline and the estimated number of incident (new) events in previously healthy by 2016 is 2,202. In addition, we work with zebrafish model systems to establish causal CHD genes and characterize their mechanisms of action.We have access to unique study materials, state-of-the art methods, and a strong track record of successful projects in this field. To our knowledge, there are no other groups combining -omics methods to elucidate the whole chain from DNA variation to overt CHD in such large and well-characterized study samples. Further, we are unaware of other groups using zebrafish models to screen for and characterize causal CHD genes. Our work is anticipated to lead to new important insights into the pathophysiology of CHD, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development.