Genetically Predicted Intervertebral Disc Degeneration and Risk of Osteoarthritis: A Two-Sample Mendelian Randomization Study with Mediation Analysis of Obesity and Sarcopenia

Abstract

Background Chronic pain related to spinal degeneration and osteoarthritis (OA) represents a major cause of disability worldwide. However, whether intervertebral disc degeneration (IVDD) contributes to OA and related pain burden remains unclear. Objective To investigate the potential causal relationship between genetically predicted IVDD-related traits and OA risk, and to explore the mediating roles of obesity and sarcopenia. Methods We conducted a two-sample Mendelian randomization study using genome-wide association study (GWAS) data. IVDD-related genetic instruments were obtained from FinnGen, and OA outcomes included knee osteoarthritis, hip osteoarthritis, and joint replacement. Sensitivity analyses were performed using multiple MR methods. A two-step MR framework was applied to assess mediation effects. Results Genetically predicted IVDD was associated with an increased risk of HOA (OR = 1.33, 95% CI: 1.20–1.48), THR (OR = 1.37, 95% CI: 1.20–1.56), and KOA (OR = 1.17, 95% CI: 1.09–1.26). Similar associations were observed for lumbar disc prolapse and sciatica, which were consistently linked to higher risks of OA outcomes. Two-step MR analyses indicated that both adiposity-, obesity-, and metabolic-related and sarcopenia-related traits partially mediated these associations. The proportion mediated by adiposity-, obesity-, and metabolic-related traits ranged from approximately 2% to 31%, while sarcopenia-related mediation ranged from 3% to 20%, depending on exposure and outcome pairs. Conclusion This study provides genetic evidence supporting a potential link between spinal degeneration and chronic pain-related osteoarthritis. Obesity and sarcopenia may serve as partial mediators, highlighting potential targets for prevention and intervention in chronic musculoskeletal pain conditions.