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

Authors

An Wang, Hongying Shan, Xi Cao, Ye Li, Xuzhao Bian, Di Zhang, Xingjie Hao, Shiquan Sun

Published in

Osteoarthritis and cartilage open. Volume 8. Issue 4. Pages 100877. Epub Sep 18, 2026.

Abstract

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.
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.
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.
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.

PMID:
42861094
Bibliographic data and abstract were imported from PubMed on 12 Oct 2026.

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