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

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.