Abstract
Osteoarthritis (OA) is a widespread degenerative joint disease. The current treatment mainly focuses on relieving symptoms, so its targeted therapy has attracted more and more attention from physicians. Multi-omics Mendelian randomization analysis provides innovative perspectives for uncovering possible therapeutic targets. This study utilized data from multi-omics analyses, including expression quantitative trait loci, protein quantitative trait loci, and methylation quantitative trait loci, combined with summary-data-based Mendelian randomization and colocalization analyses, to explore genetic markers and molecular pathways associated with OA. We also performed single-cell sequencing analysis to investigate gene expression in cartilage with OA and utilized molecular docking techniques to predict drug candidates. Finally, to explore the involvement of core proteins in OA, we carried out USP8-centered protein-protein interaction and enrichment analyses. The 4 genes linked to OA were found after integrating multi-omics results: USP8, DLK1, OMG, and SNUPN. Among them, USP8, as a first-level gene, has strong multi-omics evidence that it is closely related to OA. The other key genes identified were DLK1, OMG, and SNUPN as tertiary, quaternary, and quaternary genes, respectively. Molecular docking results showed that GDC-0134 could effectively target DLK1, which provided a new target for targeted therapy of DLK1. In addition, several genetic associations were validated in a replication cohort, and protein-protein interaction and enrichment analyses were conducted to explore the molecular networks linked to OA. The multi-omics integration identified several key genes and pathways associated with OA, providing a comprehensive understanding of the molecular mechanisms underlying the disease. USP8 and DLK1 were highlighted as promising therapeutic targets. These results offer promising avenues for creating novel therapies aimed at modifying OA progression.