Epigenetic Mediating Mechanisms in Parkinson's Disease: The Impact of Educational Attainment on SETD1A Expression

This study investigated the interplay between environmental, genetic, and epigenetic factors in Parkinson's disease (PD) etiology, aiming to identify key factors and their impact on disease progression. Leveraging genome-wide association study data of PD and environmental-related factors, in conjunction with blood expression quantitative trait loci (QTLs) and methylation QTLs data, we used two-sample Mendelian randomization (MR), summary data-based MR (SMR), and colocalization analysis to explore the association between environmental, epigenetic, and genetic factors and PD risk. We also conducted transcriptomic analysis of the targeted gene and investigated its functional mechanism in PD with mouse datasets. A meta-analysis of relevant prospective cohort studies was also conducted to validate the links between the identified environmental factor and PD risk. Five modifiable factors were identified as associated with PD, including educational attainment. SMR and colocalization analysis demonstrated 14 methylation sites linked to the expression of eight genes and PD risk. Among them, six methylation sites might affect the expression of SET Domain Containing 1A (SETD1A). Furthermore, prolonged educational attainment was found to be causally associated with hypermethylation of cg09162137, which downregulated SETD1A and impacted PD risk. Transcriptomic analysis indicated lower expression of SETD1A in PD cases. Pathway enrichment and protein-protein interaction analysis suggested that SETD1A might influence mitochondrial function and α-synuclein pathogenesis. Finally, a meta-analysis indicated that higher education levels increased PD risk (hazard ratio = 1.15) but did not affect other PD progression phenotypes except cognition. We identified five modifiable factors associated with PD. Higher education attainment might increase PD risk by affecting the expression of SETD1A. © 2025 International Parkinson and Movement Disorder Society.