Proteome-wide Mendelian randomization and transcriptome analysis of a novel osteoarthritis blood-targeting USP8, single-cell model and experimental validation.

BACKGROUND: Osteoarthritis (OA) is the most common chronic joint disorder and greatly affects quality of life and increases socioeconomic burden; however, effective prevention is limited. Blood proteins with established causal evidence can probably serve as potential drug targets, but few have been causally linked with OA. This study focused on identifying blood proteins associated with OA through genome-wide association meta-analysis, proteome-wide Mendelian randomization (PWMR), and summary-data-based Mendelian randomization (SMR) analyses to conduct preliminary validation and mechanism exploration. METHODS: A genome-wide association meta-analysis was conducted with 86,004 OA patients and 825,565 controls. Additionally, various inverse-variance weighted Mendelian randomization (MR) analyses and SMR tests were performed with cis-acting variants of 4907 blood proteins from the deCODE study (N = 35,559) and 2940 from the UKB study (N = 45,330). We subsequently validated novel proteins through single-cell data and experiments. Furthermore, we explored their potential mechanisms through transcriptomic data. RESULTS: Significant genome-wide variants (P < 5 × 10-8) were detected at 18 loci. The PWMR analysis identified 43 blood proteins potentially causally linked to OA, of which three (USP8, OGN, and OMG) passed the SMR test; USP8 also passed the colocalization test. Functional annotation revealed that many proteins are expressed in adipose tissue. Potential anti-OA drug targets were identified by genetic colocalization and druggable genome studies. Single-cell and experimental validation were consistent with the above findings. Furthermore, transcriptomic analysis provided convergent evidence by delineating specific biological processes associated with USP8 expression in OA. CONCLUSIONS: This comprehensive genome-wide association meta-analysis revealed new OA-related variants and several blood proteins with possible causal relationships with OA. These findings can contribute to a deeper understanding of the genetic basis of this disease and suggest OA-related pathways as promising targets for further therapeutic exploration.