Serum Metabolites and Parkinson‘s Disease: A Bidirectional Mendelian Randomization Study
Serum Metabolites and Parkinson‘s Disease: A Bidirectional Mendelian Randomization Study
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Original abstract
Abstract Purpose Parkinson’s disease (PD) is the second most common neurodegenerative disorder, yet its etiology remains incompletely understood. Methods Using a two-sample Mendelian randomization approach, we systematically evaluated the causal associations of 1,091 serum metabolites and 309 metabolite ratios with PD risk. Metabolite summary data were derived from a large-scale GWAS of 8,299 European individuals, while PD data came from a FinnGen meta-analysis comprising 5,861 cases and 494,487 controls. Genetic variants strongly associated with each metabolite served as instrumental variables, with inverse-variance weighting as the primary method, supplemented by multiple sensitivity analyses. Results After false discovery rate correction, 21 metabolites exhibited significant causal effects on PD: 10 metabolites, including trimethylamine N-oxide and fructosyllysine, were inversely associated with PD risk (OR range: 0.72–0.979), suggesting protective roles, whereas 11 metabolites, such as epiandrosterone sulfate and thymol sulfate, showed positive associations (OR range: 1.00–1.45), indicating potential risk factors. Reverse MR analysis revealed no significant reverse causation except for TMAO. Conclusion Our findings highlight that lipid metabolism disturbances play a pivotal role in PD pathogenesis, with additional contributions from amino acids and energy-related metabolites.These candidate metabolites may serve as promising biomarkers for early diagnosis or as therapeutic targets, providing new avenues for mechanistic research and clinical intervention in PD.