Objective: To identify gene-specific DNA methylation associated with Parkinson’s disease (PD).

Background: There is a growing interest in the role of epigenetic DNA methylation (DNAm) in iPD believed to be influenced jointly by environmental and genetic factors. We recently showed that the epigenetic (methylation) age of the immune system is significantly increased in PD patients compared with population controls and that granulocytes play a significant role. Several previous studies focused on alpha-synuclein methylation and reported that DNAm sites in SNCA intron1 are hypomethylated in PD patients compared with controls. However, findings were inconsistent across populations and tissue types, and thus far no study examined methylation genome-wide in PD.

Methods: We investigated DNAm profiles of peripheral whole blood cells from 508 Caucasians and 64 Hispanics in the Parkinson’s Environment and Gene study (335 iPD and 237 controls) using Illumina Infinium 450k microarrays. We identified associations of individual DNAm sites with PD using Pearson’s correlations and conducted a meta-analysis using Stouffer’s method to obtain Z scores and p-values across ethnic groups. The online gene set enrichment analysis tool -DAVID- provided us with gene functional annotations in PD-associated genes with DNAm sites found to be statistically significantly different in cases and controls.

Results: We identified 655 PD-associated DNAm sites in 469 genes with a genome-wide significance level of p<10-7 adjusting for age, gender and cell type composition; of these 61% were hypomethylated in PD patients. The two most highly significant methylated genes were mitochondria related. We also found one out of 26 DNAm site in SNCA intron1 to be of borderline genome-wide significance (p=5.0×10-6). Employing functional enrichment analysis, PD-associated hypomethylated genes were enriched for promoter binding (p=1.8×10-3) and metal ion binding (p=2.4×10-3), while hypermethylated genes were enriched for T cell differentiation (p=4.5×10-4). However, none of these three enrichment categories remained statistically significant after Bonferroni correction.

Conclusions: Our study provides the first evidence that links epigenetic differences specifically peripheral blood cell DNA methylation to mitochondria related genes in PD. We also found a weak signal for changes in SNCA intron1 methylation and PD using a genome-wide methylation approach in a large sample.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/epigenome-wide-association-study-of-parkinsons-disease/