Obesity-driven mechanisms are associated with the risk of developing cardiovascular and neurodegenerative diseases. Understanding which specific pathways contribute to cardiac and neuronal changes may enhance interventions for both conditions. Unraveling the impact of naturally occurring genetic variation in the human population represents an opportunity to reveal many new insights into human biology and is a promising approach to identifying novel pathways that contribute to the pathogenesis of cardiovascular and neurodegenerative diseases. In the Nath Lab, we systematically identify connections between genes and the human biology they regulate through the integration of multi-omics human datasets. Next, leveraging unique zebrafish models of human disease created in our Lab, we “retro-translate” these human findings back to the bench and use the tools of chemical biology to dissect their molecular mechanisms. Our overarching goal is to identify disease targets and develop small molecules to treat the dysregulation of metabolic pathways underlying cardiometabolic and neurodegenerative diseases.