Genetically informed search for potential osteoarthritis drug targets across the proteome

Summary Background Osteoarthritis (OA) is a leading cause of disability worldwide, yet no licensed therapies can prevent or slow its progression. We aimed to identify potential targets for disease-modifying OA drugs (DMOADs) by integrating genetic and differential protein expression (DPE) evidence. Methods We evaluated genetically predicted perturbations of plasma protein levels using cis-protein quantitative trait loci (cis-pQTLs) across three large European cohorts (UK Biobank Pharma Proteomics Project, deCODE, and Fenland) and outcome data from the Genetics of Osteoarthritis Consortium, covering 11 OA phenotypes. DPE analyses were performed in 44,789 UKB participants, comparing 2,920 protein measurements between OA cases and controls, supported by sensitivity analyses. Proteins identified through genetic and/or DPE approaches were further assessed in downstream analyses. Findings In total, 305 proteins showed evidence of association with OA through genetically predicted perturbations, with 81 supported by colocalisation across datasets. DPE analyses identified 605 proteins associated with at least one OA phenotype, of which 450 (74·4%) remained robust after sensitivity testing. Several novel targets were identified, including PPP1R9B, PCSK7, and ITIH4. Integration of both approaches prioritised 5 proteins, 4 of which demonstrated druggable potential, including 3 high-confidence candidates DLK1, TNFRSF9, and OGN. Downstream analyses highlighted key biological pathways and candidate compounds with potential for repurposing. Interpretation This large-scale study combines genetic and DPE evidence to prioritise candidate DMOAD targets. Findings reinforce established biology while revealing novel proteins and pathways, providing a foundation for therapeutic development in OA. Funding WL is supported by the Guangzhou Elite Project (project no. JY202314). SSZ is supported by The University of Manchester Dean’s Prize, Arthritis UK Career Development Fellowship (grant no. 23258). This work is supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). Research in context Evidence before this study Circulating proteins have been linked to osteoarthritis (OA) in observational studies, supporting their potential as biomarkers and drug targets. However, differential protein expression analyses are vulnerable to confounding and reverse causation. Mendelian randomisation (MR) studies using proteomic GWAS instruments have suggested causal roles for several circulating proteins in OA-related traits and highlighted druggable candidates. However, many analyses relied on earlier OA GWAS data (e.g., Genetics of Osteoarthritis Consortium 1·0) and smaller proteomic GWAS datasets, and typically did not integrate MR findings with large-scale differential protein expression. As a result, it remains unclear how well genetically predicted protein effects align with observed protein expression in OA, and how robust prioritised targets are when replicated across proteomic data from multiple cohorts. Added value of this study This study integrates large-scale proteomic MR and differential protein expression (DPE) analyses across multiple OA phenotypes using the largest datasets to date. By combining genetic evidence with observed protein dysregulation in population-based cohorts, we strengthen causal inference and improve robustness of target prioritisation. This approach allows us to distinguish proteins that are likely to play a causal role in OA from those that reflect downstream disease processes, and to highlight targets with greater translational relevance than identified by either method alone. Implications of all the available evidence Taken together, our findings support a causal role for a subset of circulating proteins in OA and demonstrates the value of integrating genetic and observational proteomic data for target prioritisation. Proteins supported by both MR and DPE are more likely to represent biologically relevant drivers of disease and actionable therapeutic targets. This integrated framework reduces false positives arising from confounding or reverse causation and provides a more reliable basis for drug development, biomarker discovery, and patient stratification in OA.