Objective: To compare baseline whole blood DNA methylation in unmedicated sporadic  Parkinson Disease (sPD) and healthy control (HC) participants from PPMI. To evaluate whole blood gene expression from candidate genes in differentially methylated regions from PD subjects and HC subjects.

Background: DNA methylation (DNAm) is one of the most common studied epigenetic processes in human disease. The primary consequence of DNAm is an effect on the regulation of gene expression. In previous work, we have described significant DNAm differences at specific CpGs between sPD and HC in the PPMI cohort. With this work, we build on these findings and extend the analysis to include RNA-sequencing (RNA-Seq) data in this cohort and its association with differential DNAm in sPD.

Method: Baseline data from sPD (n=196) and HC (n=88) were downloaded from the PPMI website (December 13,2021). The ChAMP pipeline was used to identify differentially methylated regions (DMRs). Data were corrected for batch effect and controlled for cell type. An adjusted FDR (false discovery rate) p value <0.01 was considered statistically significant for methylation analyses. Blood gene expression was obtained from the PPMI RNASeq raw read counts. Differential expression analysis was done using DESeq2, and an adjusted FDR p value <0.05 was used to select significantly differentially expressed genes.

Results: At baseline, there were 5,171 differentially methylated CpG sites (2,589 hypermethylated and 2,582 hypomethylated) between sPD and HC. There was no significant difference in age or sex between groups. We found 75 significant differentially expressed genes between sPD and HC (71 upregulated and 4 downregulated).  Integration of both differentially methylated sites and expressed genes showed 35 hypomethylated sites nearby 31 overexpressed genes, and 1 hypermethylated site nearby a single under expressed gene.

Conclusion: Our data supports that blood DNAm is associated with PD. We show differentially methylated regions (DMRs) in a group of treatment naïve sPD compared to HC individuals. Methylation data resulted in differential expression of several genes, including some that are implicated in the degradation of lysosomal proteins. Validation in independent cohorts and longitudinal data will be essential to replicate and extend these findings.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dna-methylation-is-associated-with-gene-expression-changes-in-sporadic-parkinson-disease-in-the-ppmi-cohort/