DNAJB12 mediates the causal effect of obesity on knee osteoarthritis: A mendelian randomization study

OBJECTIVE: Obesity is a major risk factor for knee osteoarthritis (KOA), but the circulating proteins that mediate this association remain unclear. We aimed to identify obesity-regulated circulating proteins that causally influence KOA risk. DESIGN: We conducted a Mendelian Randomization based proteome-wide association study (MR-PWAS) analysis to investigate circulating proteins mediating the effect of obesity on KOA. Using a two-step Mendelian randomization-based proteome-wide association design, we first tested genetically predicted obesity against 4907 circulating proteins from deCODE. Obesity-associated proteins were then instrumented using cis-pQTLs and tested for causal effects on KOA. Candidate mediators were evaluated using product-of-coefficients mediation analysis, replication datasets, tissue-specific eQTL analysis, Bayesian colocalization and multivariable MR analysis. RESULTS: Obesity causally influenced 243 circulating proteins. Among these, DNAJB12 showed a significant causal effect on KOA risk [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.24-1.95] and mediated 20.55% (95% CI 5.92-35.18%) of the obesity-to-KOA effect. Replication analyses supported the obesity-DNAJB12 and DNAJB12-KOA associations. Colocalization provided high-confidence evidence for a shared genetic signal between DNAJB12 pQTLs and KOA in the larger KOA GWAS dataset (PP·H4 = 0.9490). Multivariable MR implicated fat mass, but not fat-free mass, as the main driver of mediator protein changes and KOA risk. CONCLUSIONS: Obesity causally increases KOA risk, partially acting through obesity-regulated circulating protein DNAJB12. These findings highlight adiposity-driven pathways and fat mass reduction as potential strategies to mitigate obesity-associated KOA.