Project Summary / Abstract A total of 18.2 million people in the U.S. currently live with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Susceptibility to cardiometabolic diseases is highly variable, and currently no FDA-approved drugs exist to treat NAFLD. Recent work suggests that cardiometabolic diseases share several genetic factors, and our long-term goal is to reveal the complex interplay between genomic and non-genomic risk factors in the development of disease to improve risk prediction and identify drug targets for repurposing to treat NAFLD. In our first aim we will apply causal single and multiple causal mediation analysis in the UK Biobank to identify intermediate or moderating endophenotypes that can serve as potential intervention targets for type 2 diabetes and NAFLD. We provide a framework for precision phenotyping and quantify how much individual-level genetic burden for disease can be reduced if one would intervene on intermediary endophenotypes. It may ultimately enable clinicians to detect early departures from patient-specific baseline risk that, while themselves are still asymptomatic, are predictive of the subsequent onset of disease symptoms. Our second aim is to identify and validate drug targets for potential repurposing in NAFLD using genomic and real-world data. We will identify candidate drug targets using two approaches: 1) instrumental variable analysis using genetic instruments of the `druggable' genome (e.g., Mendelian Randomization analysis) and 2) a computational gene expression signature-based approach based on the knowledge of drug activity and disease pathophysiology. Predictive validity of drug efficacy for candidate drug targets will be assessed using real-world data of 9.1 million Veterans in the Veterans Health Administration healthcare system, 3.6 million patients in the Penn Medicine clinical data warehouse, and 3.5 million patients in the Vanderbilt Synthetic Derivative. Long-term therapeutic efficacy will be evaluated using emulated target trials in NAFLD patients with cirrhosis, hepatic decompensation, liver transplant, and liver cancer as the primary treatment endpoint during five years of follow-up. Short-term drug efficacy will be evaluated in healthy patients using self-controlled case series analysis with change in alanine transferase as the primary outcome. It is anticipated that our genomics- informed and pharmaco-epidemiological approach to drug repurposing will accelerate drug-discovery efforts and lead to the use of existing agents to treat NAFLD with shortened drug development times.