Objective: Several environmental exposures are known to affect the risk for PD. Because DNA methylation is affected by environmental variables, we investigated whether brain region-specific DNA methylation patterns differ between PD cases and controls.

Background: Genetic variations have been associated with Parkinson disease (PD), but only explain part of the disease risk. Studies have shown that there are many environmental exposures that modify the risk of PD. As DNA methylation is one the known mechanisms through which environment can influence biological process, we investigated whether methylation differences exist between PD and controls. Because DNA methylation profiles vary between brain regions, we investigated areas of the brain relevant for PD. These included the dorsal motor nucleus of the vagus (DMV), the substantia nigra (SN) and the cingulate gyrus (CG).

Methods: We investigated the association of DNA methylation patterns with PD by performing a genome-wide screen of DNA methylation on the DMV, SN and CG in 12 autopsy-confirmed PD and 11 autopsy-confirmed controls. We used Illumina 450K beadchips to interrogate gene promoters and CpG islands.

Results: We found 9,621 CpG sites that were differentially methylated between PD and controls at false discovery rate (FDR) of <0.05 and absolute differential methylation (|ΔM|) of ≥ 1.5 fold in the DMV, with none and 1 CpG site differentially methylated in the SN and CG, respectively. The methylation status of neighbor CpG sites has been shown to be highly correlated, leading to the identification of differentially methylated regions (DMRs), which are less subject to identification artifacts than single CpG site methylation. We identified 1,775 DMRs in the DMV (FDR<0.05), including some in genes previously reported as associated to PD, like MAPT. A combined analysis of both methylation and RNA-seq data revealed 90 genes with significant DMRs that were also significantly differentially expressed. Pathway analysis of these genes showed significant enrichment for synaptic or neurotransmitter function (P value < 0.001).

Conclusions: Our data suggest that an epigenetic-load mechanism affecting genes involved in neurotransmission and synaptic pathways is a likely factor in neurodegenerative processes of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-dna-methylation-analysis-reveals-epigenetic-perturbations-in-parkinson-disease/