This research proposal, entitled "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium", will leverage existing population, laboratory and computational resources to identify susceptibility genes underlying genome-wide significant and well-replicated GWAS findings for heart, lung and blood diseases and their risk factors. The U.S. CHARGE consortium consists of multiple large population-based longitudinal cohort studies, including the Atherosclerosis Risk in Communities (ARIC) Study N=15,792, the Cardiovascular Health Study (CHS) N=5,888, and the Framingham Heart Study (FHS) N=14,428. Additionally, the Coronary Artery Risk Developments in Young Adults (CARDIA N=3,756) study has joined this collaborative effort. For each of these cohorts, DNA samples have already been isolated and the phenotype data are readily available for analysis. The proposed research will take a two pronged approach to following-up GWAS: First, we will carry-out targeted sequencing and replication genotyping in 60 genomic regions influencing 15 phenotypes. For each phenotype, we will sequence 400 cases for discrete phenotypes or the top 10% for quantitative phenotypes and 400 controls or bottom 10%. Second, we will take a first step toward illuminating the dark matter of unaccounted-for genetic variance for one model phenotype (i.e. HDL cholesterol) by whole genome sequencing of 230 African-American ARIC participants selected from the top and bottom 10% of the HDL-cholesterol distribution. Discoveries based on sequence analysis in one sample will be validated by genotyping in additional samples. State-of-the-art computational models designed specifically for next generation sequence data will be used for quality assurance, population genetic, and genotype-phenotype analyses. The research infrastructure for this project is already in place as a result of ongoing collaborations among genomic scientists, physicians, epidemiologists and population and statistical geneticists. This project will not only enhance our understanding of the genetic architecture of multiple phenotypes of public health importance, but it will also benefit the broad scientific community by making these sequence and phenotype data available via dbGaP. Public Health Relevance Statement: "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium" will leverage existing resources to identify genes underlying genome-wide significant and well-replicated GWAS findings for heart, lung and blood diseases. We will carry-out targeted resequencing (400 cases and 400 controls) in 60 genomic regions influencing 15 phenotypes. Second, we will take a first step toward illuminating the dark matter of unaccounted-for genetic variance for one model phenotype (i.e. HDL cholesterol) by whole genome sequencing of 230 African-Americans selected from the top and bottom 10% of the HDL-cholesterol distribution.