The Causal Effects of Lifestyle Factors on Osteoarthritis: A Two-sample Mendelian Randomisation Study

Background: Modern sedentary lifestyles are prevalent among individuals with osteoarthritis. However, direct evidence linking such behaviours as causative factors of osteoarthritis remain limited due to the presence of confounding variables. Objective: This study aims to determine the extent to which lifestyle factors have causal effects on osteoarthritis through a two-sample Mendelian randomisation (MR) study. Methods: Exposure-outcome relationships were evaluated using inverse variance weighted twosample MR and summary statistics of genome-wide association studies of lifestyle factors and osteoarthritis. Weighted median, MR-PRESSO, and MR-Egger regression were used as sensitivity analyses. We obtained causality estimates, 95% confidence intervals (CI), and P-values from each MR method. Steiger filtering and radial filtering were used to exclude SNPs demonstrating reverse causality and significant heterogeneity, respectively. Results: MR analyses demonstrated that certain lifestyle factors had causal effects on osteoarthritis, particularly insomnia (OR 1.09 (0.387-1.79), P = 0.0024), BMI (OR 6.45 (4.48-8.42), P = 1.38e-10) and protein intake (OR 2.94 (0.361-5.52), P = 0.026). Effects were consistent across sensitivity analyses using median-based MR methods. ZNF131 & SEMA3F, and potentially RWDD2B & USP8 are genetic loci identified to mediate these causal effects. Conclusion: Our results illustrate that lifetime exposure to certain lifestyle factors has causal effects on osteoarthritis. Further studies are required to determine the efficacy of lifestyle-based interventions in reducing the population-wide disease burden of osteoarthritis.