• Plasma metabolites show causal associations with specific osteoarthritis subtypes, particularly weight-bearing joints.
• Glycine, serine, higenamine, and sulfate are key metabolites linked to multiple osteoarthritis types.
• No significant causal associations were found for finger, hand, hip, and spinal osteoarthritis after FDR correction.
• The study provides a methodological framework for Mendelian randomization in complex disease research.