Serum total cholesterol and low-density lipoprotein cholesterol are associated with Parkinson’s disease in East Asian populations: a bidirectional Mendelian randomization study with complementary animal observation

Abstract

Background Dysregulation of lipid metabolism has been implicated in Parkinson’s disease (PD), yet causal relationships remain unclear due to confounding factors inherent in observational studies. Most Mendelian randomization studies on lipid-PD relationships have been conducted in European populations, leaving the causal association in East Asian populations largely unexplored. Methods We conducted a bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data from the Integrative Epidemiology Unit (IEU) Open GWAS project for East Asian populations to assess the causal associations between four lipid traits — triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)—and PD. The primary MR analyses were conducted using the inverse-variance weighted (IVW) method. Sensitivity analyses included Cochran’s Q test, MR-Egger regression, and leave-one-out analyses. We further conducted colocalization analysis to assess whether the four lipid traits and PD shared common genetic variants. Finally, we complemented the findings using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Results Genetically predicted higher levels of TC (OR = 0.476, 95% CI = 0.269–0.843, p = 0.011) and LDL-C (OR = 0.494, 95% CI = 0.289–0.845, p = 0.010) were associated with a reduced risk of PD. No causal relationship was observed between TG or HDL-C and PD. Reverse MR analysis indicated no causal effect of PD on any of the lipid traits. Colocalization analysis did not support shared genetic variants between the lipid traits and PD (all PP.H4 < 0.8). In MPTP-induced PD mice, both TC and LDL-C levels were significantly lower than in controls. Conclusion This study provides genetic evidence supporting a genetically predicted inverse association of TC and LDL-C with PD risk among East Asian populations. The underlying mechanisms and any therapeutic implications warrant further experimental investigation.