Integrative Metabolomics-GWAS Mendelian Randomization Reveals Causal Metabolic and Inflammatory Drivers of Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by a complex pathogenesis involving the interplay of multiple molecular and cellular pathways. In recent years, metabolic dysregulation and neuroinflammation have been recognized as key contributors to PD onset and progression, potentially mediating neurodegenerative changes by affecting dopaminergic neuron survival, synaptic function, and neural network homeostasis. However, conventional observational studies are limited in establishing causal relationships between these metabolites and inflammatory mediators, highlighting the urgent need for systematic identification using genetic approaches.
Meathods
Using Mendelian randomization, this study systematically elucidates, for the first time, the causal roles of key metabolites and inflammatory mediators in PD. These findings provide critical genetic evidence for the identification of early biomarkers and the development of potential therapeutic targets, while also offering novel insights into the mechanistic interplay between metabolic dysregulation and inflammation in neurodegenerative diseases.
Result
A total of 722 differential metabolites were identified, of which three had corresponding genetic information in GWAS datasets. In addition, 14 caffeine-related metabolites and 91 inflammatory mediators were included in the MR analysis. The results showed that 1-Methylnicotinamide, Flt3L, IL-13, and ST1A1 were negatively associated with PD, suggesting potential protective effects, whereas FGF-5, IL-4, and CCL13 exhibited positive causal associations, indicating potential risk-promoting roles. These findings highlight the central role of inflammatory pathways in PD pathogenesis and progression and suggest a potential interplay between metabolic dysregulation and inflammatory responses.
Conclusion
This study, using Mendelian randomization, systematically elucidates for the first time the causal roles of key metabolites and inflammatory mediators in PD, providing critical theoretical evidence for the identification of early biomarkers and the development of potential therapeutic targets, while also offering novel genetic insights into the mechanistic interplay between metabolic dysregulation and inflammation in neurodegenerative diseases.