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.

The authors thank all participants and their families, as well as the investigators and research teams of the SGPD cohort, PEG1 study, PEG2 study, and PPMI cohort, for contributing their time, data, and biological samples, without which this study would not have been possible. The authors are grateful to Dr. Jianming Zeng (University of Macau) and members of his bioinformatics team, biotrainee; Dr.

Jun Zhang (School of Life Science and Technology, China Pharmaceutical University); Dr. Kaifeng Hu (West China Second University Hospital, Sichuan University); and Wenyan Chen (orange_milk_sugar) for generously sharing their experience and code. The authors also acknowledge the funders that supported the original cohorts and the present study.

The Queensland Parkinson’s Project (QPP) of the SGPD cohort was supported by a grant from the Australian National Health and Medical Research Council (1084560) to G.M. The New Zealand Brain Research Institute (NZBRI) cohort of the SGPD cohort was funded by a University of Otago Research Grant, together with financial support from the Jim and Mary Carney Charitable Trust, Whangarei, New Zealand. The PEG study was funded by the National Institute of Environmental Health Sciences project “Environmental exposure, DNA methylation, and Parkinson’s disease” (R21 ES024356, to S.