AIMS: Osteoarthritis (OA) is a widespread chronic degenerative joint disease with an increasing global impact. The pathogenesis of OA involves complex interactions between genetic and environmental factors. Despite this, the specific genetic mechanisms underlying OA remain only partially understood, hindering the development of targeted therapeutic strategies. METHODS: A transcriptome-wide association study (TWAS) was conducted for site-specific OA phenotypes using functional summary-based imputation (FUSION). High-confidence candidate genes were identified through rigorous quality control measures, including joint/conditional analysis, permutation tests, best model evaluation, and colocalization analysis. Co-expression network analysis was performed to elucidate the functional biology of these candidate genes. Druggable gene targets and their structural models were retrieved from the DrugBank and SWISS-MODEL databases. Finally, the enrichment of mitogen-activated protein kinase 3 ( RESULTS: Utilizing the FUSION algorithm, TWAS identified 794 candidate genes for OA. After quality control, 14 genes were classified as high-confidence genes, with seven recognized as potential drug targets including CONCLUSION: The present study identified tissue-specific candidate genes and validated high-confidence druggable targets for OA, providing new insights into the genetic landscape and biological processes involved in OA. Further functional studies are warranted to confirm these findings.