Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease

Abstract

Objective: Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls.

Methods: DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area.

Results: Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak p < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01).

Conclusions: Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.

Figure. PD-associated DMRs

(A) DMRs previously identified in the discovery data set were also significantly differentially methylated in the same direction in the replication data set. The SN is not included because we did not detect overlap at the DMR or gene level with any of the other 2 tissues. (B) Common PD-associated DMRs identified in the 3 analyzed tissues in the joint analysis. A DMR in LOC100420587, an SHC binding and spindle associated 1 pseudogene, is present in all 3 regions. If DMRs could be assigned to more than 1 gene, both genes are shown separated by a slash. Asterisks denote overlap at the gene level but not at the DMR level (distinct DMRs assigned to the same gene). In the Venn diagram, the numbers are the significant DMRs in the 2 data sets/brain regions and those shared between them. Brackets besides gene names indicate the genomic location of the DMR. CG = cingulate gyrus; DMR = differentially methylated region; DMV = dorsal motor nucleus of the vagus; GB = gene body; PD = Parkinson disease; Pr = promoter; SN = substantia nigra; Upst = upstream intergenic region.