Exploring the Causal Link Between Plasma Lipidome and Trigeminal Neuralgia Using Bidirectional Mendelian Randomization

<b>Background:</b> Trigeminal neuralgia (TN) is a prevalent neurological disorder characterized by recurrent acute pain localized within the distribution area of the trigeminal nerve. This condition places a severe psychological and emotional burden on patients. Although lipids are associated with many diseases, their relationship with TN remains unclear. This study aims to investigate the causal association between plasma lipidome and TN using a bidirectional two-sample Mendelian randomization (MR) approach, with the ultimate goal of informing potential therapeutic strategies for TN management. <b>Methods:</b> We conducted a bidirectional two-sample MR analysis to systematically assess the causal relationship between plasma lipidome and TN. Genome-wide association study (GWAS) summary statistics for plasma lipidome and TN were obtained from publicly available datasets. The primary causal inference was performed using inverse variance weighted (IVW) regression, with complementary analyses including MR-Egger regression, weighted mode, simple mode, weighted median, and MR pleiotropy residuals and outliers (MR-PRESSO) to test for and adjust potential pleiotropy. Comprehensive sensitivity analyses were implemented to verify the robustness of our findings, including heterogeneity testing, leave-one-out analysis, and examination of directional pleiotropy. This multianalytical approach provides a rigorous framework for elucidating the potential role of plasma lipidome dysregulation in TN pathogenesis. <b>Results:</b> Our forward MR analysis results demonstrated that genetically predicted glycerophospholipids (GP) and glycerolipid family (GL) exert significant causal effects on TN risk. More specifically, phosphatidylinositol (PI) in the GP, as well as diacylglycerol and triacylglycerol in the GL, were significantly associated with reduced TN risk (<i>p</i> < 0.05, OR < 1). However, distinct molecular configurations of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) within the GP class exhibited differential impacts on TN susceptibility. The reverse MR analysis identified eight configurations of PC reduced TN risk (<i>p</i> < 0.05, OR < 1), with PC (18:0_18:2) showing a particularly notable bidirectional causal relationship with TN. Rigorous sensitivity analyses confirmed the absence of both heterogeneity (Cochran's <i>Qp</i> > 0.05) and horizontal pleiotropy (MR-Egger intercept <i>p</i> > 0.05) across all examined lipid species, supporting the robustness of these findings. <b>Conclusions:</b> This MR study establishes causal links between specific plasma lipidomes and TN risk, identifying protective lipid species and revealing a bidirectional relationship for PC, offering potential therapeutic targets for TN management.