Epigenome-wide meta-analysis of sex-differential DNA methylation in Parkinson’s disease

Sex differences are recognized in Parkinson’s disease (PD), but their epigenetic basis remains incompletely understood. We performed a two-stage epigenome-wide meta-analysis of DNA methylation to characterize sex-differential methylation profiles in PD. The discovery stage included blood samples from 1143 patients with PD and 1013 matched healthy controls from two independent datasets. The validation stage integrated longitudinal DNA methylation, transcriptomic, and clinical data from the Parkinson’s Progression Markers Initiative cohort and assessed cross-tissue consistency using saliva samples and in silico blood–brain methylation concordance analyses. We identified 2199 PD-unique sex-differentially methylated positions and 365 PD-unique sex-differentially methylated regions, with males generally showing lower methylation levels than females. Genes annotated to these loci were enriched in neurodevelopmental and synaptic processes, and candidate hub genes included PINK1 , BCL2 , and MAPK1 . Longitudinal validation supported the relative stability of sex-differential methylation patterns during PD progression. These findings provide a candidate sex-differential DNA methylation resource for future sex-aware biomarker and mechanistic studies. Prospective clinical validation and functional experiments are required before translational application.