PROJECT SUMMARY / ABSTRACT Chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, is a heterogeneous syndrome. Comprehensive insight into COPD heterogeneity requires longitudinal data to elucidate the genetic, clinical, and radiographic determinants of disease progression. This proposal will extend the COPDGene Study by performing ten-year longitudinal follow-up visits on all available COPDGene subjects, with follow-up chest CT scans. The primary goals of COPDGene are: a) To identify new genetic loci that influence the development of COPD and COPD-related phenotypes; b) To reclassify COPD into subtypes that can ultimately be used to develop effective subtype-specific therapies; and c) To translate the findings in COPDGene to improve diagnostic and prognostic approaches to COPD in general clinical populations. The primary hypothesis for this renewal application is that extensive genetic and longitudinal phenotypic data in subjects with COPD or at risk for COPD will enable creation and validation of a new classification system for COPD with distinct diagnostic and prognostic implications. The specific aims are: 1) To evaluate progression of COPD by completing a ten-year follow-up of all available subjects in the COPDGene cohort using clinical phenotyping and both quantitative and visual analysis of chest CT scans; 2) To use whole genome sequencing analysis on the COPDGene cohort to identify both rare and common genetic determinants of susceptibility and progression of disease in COPD subtypes and to create effective genetic risk scores for COPD; and 3) To translate COPDGene findings on COPD subtypes and genetics to general clinical populations by interaction with clinical Lung Cancer Screening Programs. It is anticipated that whole genome sequencing analysis will be completed on the entire COPDGene cohort through the TOPMed program. This data in combination with ten-year longitudinal clinical data and CT imaging data on the cohort is expected to enable identification of novel genetic associations for unique COPD subtypes. The long-term goal is to enable enhanced diagnostic, prognostic and therapeutic approaches for personalized therapy in COPD.