Objective: Compare baseline whole blood DNA methylation in unmedicated idiopathic Parkinson’s Disease (iPD) and healthy control (HC) participants from PPMI

Background: Epigenetic mechanisms like DNA methylation (DNAm) modulate the brain transcriptome and have key roles in neurodegeneration [1]. Environmental exposure and dopaminergic therapy can alter methylation profiles, and several studies link aberrant DNA methylation with PD pathology [2-6].

Method: Baseline data from iPD (n=196) and HC (n=88) were downloaded from the PPMI website (December 13,2021). Data used in the preparation of this article were obtained from the PPMI database (www.ppmi-info.org/access-dataspecimens/download-data). For up-to-date information on the study, visit ppmi-info.org. The ChAMP pipeline [7] was used to identify differentially methylated probes (DMPs) and differentially methylated regions (DMRs). Data were corrected for batch effect and controlled for cell type. We utilized β-values to calculate age acceleration (DNAm age minus chronological age). An adjusted (false discovery rate) p value <0.05 was considered statistically significant for all analyses.

Results: There were no significant differences in age, female to male ratio, or ancestry between iPD and HC. HC had a significantly higher Montreal Cognitive Assessment (MoCA) score. No data was available on environmental and lifestyle factors. At baseline, we identified 5171 differentially methylated sites between iPD and HC subjects. The three top canonical pathways enriched in PD subjects included focal adhesion, phosphatidylinositol signaling system and Ras signaling pathway [Figure 1]. We also identified 13 differentially methylated regions [Table 1]. Finally, 57% of PD subjects presented age acceleration greater than 3 years. Linear regression showed that age acceleration at baseline was significantly associated with the age of symptom onset (OR=5.47 (95%CI 4.96 – 6.03); p < 2e -16).

Conclusion: We identified multiple genomic methylation sites and regions showing significant differences between iPD and HC. The novelty of our data is that analysis was performed on a large number of treatment naïve iPD participants. Our data also suggests that methylation changes are associated with the age of symptom onset. Validation in independent cohorts and longitudinal data will be essential to replicate and extend these findings.

References: [1] Urbizu A, Beyer K (2020) Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy. Int J Mol Sci 21.
[2] Figge DA, Eskow Jaunarajs KL, Standaert DG (2016) Dynamic DNA Methylation Regulates Levodopa-Induced Dyskinesia. J Neurosci 36, 6514-6524.
[3] Masliah E, Dumaop W, Galasko D, Desplats P (2013) Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 8, 1030-1038.
[4] de Boni L, Riedel L, Schmitt I, Kraus TFJ, Kaut O, Piston D, Akbarian S, Wullner U (2015) DNA methylation levels of alpha-synuclein intron 1 in the aging brain. Neurobiol Aging 36, 3334 e3337-3334 e3311.
[5] Kaut O, Schmitt I, Wullner U (2012) Genome-scale methylation analysis of Parkinson’s disease patients’ brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1. Neurogenetics 13, 87-91.
[6] Rawlik K, Rowlatt A, Tenesa A (2016) Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson’s Disease. Genetics 204, 771-781.
[7] Tian Y, Morris TJ, Webster AP, Yang Z, Beck S, Feber A, Teschendorff AE (2017) ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics 33, 3982-3984.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dna-methylation-differs-between-idiopathic-parkinson-disease-and-healthy-control-subjects-in-the-parkinsons-progression-marker-initiative-ppmi-cohort/