Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data.
BACKGROUND Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Lipid metabolism is closely related to neuronal function and energy homeostasis, but the genetic association between specific lipid species and ALS risk remains unclear. OBJECTIVE This study aimed to investigate the potential causal associations between genetically predicted lipid species and ALS risk using a two-sample Mendelian randomization (MR) approach. METHODS Summary-level GWAS data for 179 lipid species were obtained from 7,174 Finnish participants in the GeneRISK cohort. ALS GWAS data included 29,612 ALS cases and 122,656 controls. The inverse variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. False discovery rate (FDR) correction was applied across all lipid traits based on IVW P values. Sensitivity analyses were conducted to assess heterogeneity, horizontal pleiotropy, and robustness. RESULTS After FDR correction, genetically predicted higher levels of diacylglycerol (DAG) (18:1_18:1), phosphatidylcholine (PC) (16:1_18:1), PC (18:0_18:1), phosphatidylethanolamine (PE) (O-16:1_18:2), and several triacylglycerol (TAG) species were associated with increased ALS risk. Phosphatidylinositol (PI) (16:0_18:1) showed only a nominal protective association and did not remain significant after FDR correction. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy. CONCLUSION This MR study provides genetic evidence supporting potential associations between specific lipid species and ALS risk. These findings highlight lipid metabolism as a relevant pathway in ALS susceptibility.