Genetic Associations of Lipid-Lowering Drugs and Parkinson’s Disease: A Mendelian Randomization Study

Abstract

Background: There is a need to establish the role of lipid-lowering agents as a therapeutic option for Parkinson's Disease (PD), but its associations remain elusive. This study investigated genetic variants proxying lipid-lowering agents through HMGCR, NPC1L1, and PCSK9 inhibitors to determine casual associations with PD risk. Methods: We utilized a two-sample Mendelian randomization (MR) framework, where low-density lipoprotein (LDL) was the outcome of interest. Genetic associations with LDL were extracted from the Global Lipids Genetics Consortium. Summary statistics for PD were extracted from two GWAS datasets, consistent of 1,843 PD cases and 216,630 control in the first dataset and 1,570 PD cases and 1,259 controls in the second dataset. Instrumental variables (IV) were optimized with positive control analyses on cardiovascular and metabolic outcomes. IV-exposure associations from LDL GWAS data were integrated with IV-outcome associations from the PD GWAS data. The inverse variance weighted method was applied. Bayesian colocalization analysis identified target gene regions for LDL and PD. Results: Genetic variations in HMGCR were significantly associated with a reduced risk of PD (odds ratio [OR] = 0.54, 95% CI 0.34-0.86). However, variation in HMGCR was associated with an increased risk of the tremor-dominant (TD) subtype compared to the postural instability/gait difficulty (PIGD) subtype (OR = 8.43, 95% CI 2.12-33.52). There were trends with increased risk for the TD subtype in NPC1L1 and a decreased risk in PCSK9 but these findings did not meet the Bonferroni threshold. We identified two single nucleotide polymorphisms (SNPs) in HMGCR within the same genomic region of close proximity, with rs12916 as the leading SNP associated with LDL and rs10942735 as the leading SNP associated with PD. Conclusion: A casual association between HMGCR inhibition and reduced overall PD risk was identified, but there were increased the risks of tremor-dominant subtypes.