Proteome-Wide Mendelian Randomization Identifies Novel Plasma Protein Targets in Osteoarthritis

INTRODUCTION: Osteoarthritis (OA) is a highly prevalent chronic joint disorder and a major cause of disability worldwide, yet effective disease-modifying therapies remain unavailable. We aimed to identify plasma proteins causally associated with OA risk to screen potential therapeutic targets. METHODS: We conducted a large-scale proteome-wide Mendelian Randomization (MR) analysis by integrating Genome-Wide Association Study (GWAS) data from over 200,000 OA cases and 1,000,000 controls with protein Quantitative Trait Loci (pQTL) data for nearly 3,000 plasma proteins from 5 large proteomic studies. Causal relationship was further validated by Bayesian colocalization, summary data-based MR (SMR), and the Heterogeneity in Dependent Instruments (HEIDI) test. Single-cell RNA sequencing of OA cartilage was analyzed to characterize cell-type-specific expression patterns and the associations of prioritized proteins with senescence. RESULTS: We identified 9 plasma proteins significantly associated with OA risk, among which inter-α-trypsin Inhibitor Heavy Chain 4 (ITIH4) emerged as the most robust candidate, passing all applicable validation analyses and showing consistent associations across GWAS cohorts. ITIH4 expression was enriched in prehypertrophic chondrocytes and fibrochondrocytes, and its high-expression cell clusters exhibited significantly elevated senescence activity. DISCUSSION: These findings indicate that genetically elevated ITIH4 levels are associated with OA risk and with increased senescence signatures in chondrocytes, suggesting a potential association between ITIH4 and cartilage degeneration. CONCLUSION: Our study identifies ITIH4 as a potential biomarker and therapeutic target for OA, demonstrating the utility of integrative proteome-wide MR and single-cell analyses for target discovery.