Genetically Predicted Circulating Lipid Traits and Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study

Background: Observational studies examining the relationship between serum lipids and primary open-angle glaucoma (POAG) have yielded inconsistent findings, limiting causal inference. Mendelian randomization (MR) offers a robust approach to evaluate causality by leveraging genetic variants as proxies for modifiable exposures, thereby minimizing confounding and reverse causation. Methods: A two-sample MR study was conducted using GWAS summary statistics for 179 circulating lipid traits (GCST90277238–GCST90277416) as exposures and POAG cases from the FinnGen consortium (Release R12, endpoint H7_GLAUCOMA_POAG) as the outcome. Genetic variants were selected as instrumental variables at p < 1 × 10−5 and clumped for linkage disequilibrium (R2 < 0.001). The inverse variance weighted (IVW) method was the primary analysis. Multiple testing was addressed using both Bonferroni and false discovery rate (FDR) correction. Instrument strength was assessed via F-statistics for all 179 traits. Sensitivity analyses included MR-Egger regression, weighted median, weighted mode, MR-PRESSO, Cochran’s Q, and leave-one-out analysis. Results: Of 179 lipid traits analyzed, one, phosphatidylcholine (16:0/18:1), demonstrated a statistically significant protective association with POAG after FDR correction (β = −0.22, SE = 0.06, OR = 0.80, 95% CI: 0.71–0.90; p = 1.77 × 10−4, FDR q = 0.032). No other lipid trait survived multiple testing correction. Sensitivity analyses showed no evidence of horizontal pleiotropy or significant heterogeneity. Conclusions: This study provides genetic evidence for a protective association between phosphatidylcholine (16:0/18:1) and POAG risk; however, conditional analyses indicate this association is not fully independent of genetically correlated lipid species, and species-level specificity remains to be formally established. Phosphatidylcholine (16:0/18:1) warrants further investigation as a potential causal factor in glaucoma pathogenesis.