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Uncovering Causal Genetic Mediators Linking Redefined Obesity to Osteoarthritis: Multidimensional Analysis from Population to Genetic Mechanisms.

Tengyun Yang,Chao Jia,Guoliang Wang,Wen Zhang,Boheng Zhu,Xia Li,Leijie Chen,Yanlin Li,Zhaowei Teng

Published 2025 in Osteoarthritis and Cartilage

ABSTRACT

OBJECTIVE To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. DESIGN We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8,981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25% in men and ≥ 32% in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. RESULTS Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95%CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95%CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. CONCLUSIONS Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA.

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