Objective: To comprehensively characterize the blood-based DNA methylation alterations related to sex in patients with Parkinson’s disease (PD), shedding light on the underlying genes and biological processes that may be implicated in sex differences in PD.

Background: Sex generally modifies the vulnerability and progression of PD, with men at a higher risk of developing the disease and experiencing an earlier age of onset as well as more severe motor symptoms compared to women. Sex differences in DNA methylation have received certain attention in both health and disease conditions. However, sex-differential DNA methylation profiles are largely unknown in PD.

Method: The same analytical pipeline and inverse variance-weighted meta-analysis procedure were applied to analyze DNA methylation data (450K array) from 1143 PD patients and 1013 matched healthy controls (HC) respectively, to identify differential methylated positions (DMPs) between males and females. Gene set enrichment analysis was further conducted to explore the biological pathways associated with genes exhibiting significant sex-differential methylation levels.

Results: In meta-analysis of PD patients, 3025 significant sex-DMPs were identified, of which 2199 were unique to PD and the remaining 826 were shared with HC. Of the 2199 PD-specific sex-DMPs, 1855 (annotated to 894 gene promoters) showed lower methylation levels in males than in females, while the remaining 344 (annotated to 82 gene promoters) showed higher levels in males compared to females. In the gene ontology analysis of these differentially methylated genes, the biological processes that showed the most significant enrichment were pattern specification process (FDR=0.0002), axon development (FDR=0.0009), and axonogenesis (FDR=0.001). The most significant molecular function was DNA-binding transcription activator activity (FDR=0.02), while the most significant cellular component was neuronal cell body (FDR=0.002).

Conclusion: Our study revealed substantial blood-based sex-differential DNA methylation in PD patients. Genes with sex-differential methylated levels were predominantly enriched in neuronal cell bodies and involved in axon development and formation. These findings not only provide valuable insights into the epigenetic mechanisms underlying sex bias in PD, but also offer new opportunities for the development of biomarkers and precision medicine interventions tailored to sex differences in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/epigenome-wide-meta-analysis-of-sex-differential-dna-methylation-in-parkinsons-disease/