Plasma lipidome, circulating inflammatory proteins, and Parkinson's disease: a Mendelian randomization study

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Metabolomics

Background:

• Observational studies suggest plasma lipidome alterations are associated with Parkinson's disease (PD).
• The specific lipids influencing PD and their mechanisms remain unclear.
• The role of circulating inflammatory proteins as mediators in the lipidome-PD pathway requires investigation.

Purpose of the Study:

• To investigate the causal relationships between plasma lipidome and Parkinson's disease (PD).
• To explore the potential mediating role of circulating inflammatory proteins in the association between plasma lipidome and PD.

Main Methods:

• Utilized Mendelian randomization with single nucleotide polymorphisms (SNPs) associated with 179 plasma lipids as instrumental variables.
• Employed multiple statistical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO for robust causal inference.
• Analyzed the causal links between 91 circulating inflammatory proteins and PD, and tested for mediation effects.

Main Results:

• Identified three phosphatidylcholines associated with reduced PD risk and one sphingomyelin associated with increased PD risk.
• Found associations between several inflammatory proteins and PD risk, with FGF21, TGF-α, and TNFRSF9 linked to lower risk, and IL-17A and TNF-β to higher risk.
• Demonstrated that Fibroblast Growth Factor 21 (FGF21) may mediate the relationship between Phosphatidylcholine (14:0_18:2) and PD, explaining approximately 18% of the total effect.

Conclusions:

• Both plasma lipidome and circulating inflammatory proteins exhibit a causal link with Parkinson's disease.
• Circulating inflammatory proteins may act as mediators in the pathway connecting plasma lipidome to PD.
• Findings offer insights for PD prediction, diagnosis, and the development of novel therapeutic strategies.