Unveiling the causal effects of phosphatidylethanolamine (18:1_0:0) via glutamine conjugate of C₆H₁₀O₂ (2) and X-23648 in Parkinson’s disease: insights from mediation Mendelian randomization

The effects of lipidome and its metabolites on Parkinson’s disease (PD) have not been fully elucidated. This study aimed to assess the causal effects of lipidome on PD and the mediated effects of metabolites using Mendelian randomization (MR). Datasets of the lipidome, metabolites, and PD were acquired from genome-wide association studies, and single nucleotide polymorphisms were screened according to the basic assumptions of MR. Subsequently, inverse variance weighted was used as the main tool to assess the causal effects of lipidome on PD and the mediated effects of metabolites. Finally, the MR-Egger intercept, Cochran’s Q test, and leave-one-out sensitivity analysis were used to assess the horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. The MR analysis showed that phosphatidylethanolamine (18:1_0:0) reduced genetic susceptibility to PD by lowering glutamine conjugate of C6H10O2 (2) levels (mediated proportion: 15.80%; mediated effect: −0.024, 95% confidence interval [CI] −0.046 to −0.001, p = 0.040) and increasing X-23648 levels (mediated proportion: 15.20%; mediated effect: −0.022, 95% CI −0.045 to −0.001, p = 0.030). The MR-Egger intercept showed no horizontal pleiotropy (p ≥ 0.05) for these results. Cochran’s Q and sensitivity analyses showed that the results were not heterogeneous and were robust. Our findings indicate that phosphatidylethanolamine (18:1_0:0) reduces the risk of PD by regulating glutamine conjugate of C6H10O2 (2) and X-23648, providing genetic insights into the pathogenesis of PD. However, these results are based on European populations and require further experimental validation.