PROJECT ABSTRACT Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent a new drug class that have recently arisen to the forefront of the treatment algorithm for type 2 diabetes (T2D) due to their glycemic, metabolic, and cardiovascular benefits. However, their use has been hampered by gastrointestinal side effects. This proposal aims to understand the genetic predictors of GLP-1 RA response in order to target treatment to those most likely to benefit and avoid unnecessary exposure to those who are likely to experience intolerance. In Aim 1, the candidate will harness the phenotypic and genotypic data available in several biobank-linked electronic health records (EHR) to perform pharmacogenetic analyses. Outcomes of GLP-1 RA response will be curated using best practices and a genome-wide approach will test associations between genetic variation and phenotypes of GLP-1 RA response, with subsequent replication of genetic findings to be conducted in additional human cohorts. Aim 2 will focus on the creation of a drug perturbation trial with oral semaglutide in healthy individuals for the purposes of characterizing the acute biochemical response, as measured by changes in glucose and insulin levels in response to a mixed meal tolerance test. Subsequently, this protocol will be implemented in Aim 3 to assess how the acute response to oral semaglutide differs by genetic variation to generate insight into underlying drug mechanism and T2D pathophysiology. The candidate will complete the proposed work under the primary mentorship of Dr. Jose Florez, Chief of the Endocrine Division and Diabetes Unit at Massachusetts General Hospital (MGH) and an internationally recognized leader in clinical translation of genetic discoveries in T2D. Dr. Jordan Smoller will serve as a co-mentor due to his expertise on the application of EHR-based biobanking for genomic research and active leadership roles in the Mass General Brigham Biobank and the All of Us Research Program. Dr. Li will undertake coursework on bioinformatics and phenotype curation, expand on her experiences in studying complex trait genetics, develop knowledge in clinical pharmacology, refine her expertise in physiologic investigation, gain practical skills in clinical trial implementation, and receive periodic feedback from a research advisory committee with complementary areas of expertise. This application reflects a carefully planned training program directed at equipping the applicant with the tools necessary to conduct future pharmacogenetic studies in T2D and advancing the scientific career of the applicant toward independence. If successful, this proposal will generate evidence for precision medicine in T2D and serve as the foundation for a future pharmacogenetics trial of genotype-guided therapeutic selection for GLP-1 RAs.