Characterization of baseline and longitudinal DNA Methylation in patients with sporadic Parkinsons disease

Parkinson Disease (PD) prevalence is expected to double by 2040. Presently, it appears that the complex interplay between genetic and environmental factors underlies the pathogenesis of PD. Some of the features of PD risk may be reflected in the epigenome, which serves as an interface between genetic and environmental risk factors. DNA methylation (DNAm) is the most widely studied epigenetic phenomenon. As such, there is growing interest in exploring the role of DNAm in PD. Using data from the Parkinson Progression Markers Initiative (PPMI), we characterized cross-sectional and longitudinal DNAm differences between individuals with sporadic (i.e., non-genetic) PD and healthy controls (HC). This analysis revealed 81,604 differentially methylated positions (DMPs) and 5,281 differentially methylated regions (DMRs) between sPD and HC. Gene ontology analysis revealed that these DMPs/DMRs were associated with genes involved in diverse cellular processes, including several with specific functions in the brain ("Focal adhesion", "Cholinergic synapse", "Glutamatergic synapse", "Dopaminergic synapse"). Integration of both differentially methylated sites and expressed genes showed 20 genes that were hypomethylated and overexpressed and one gene, CTSH that was hypermethylated and associated with reduced expression. Our study provides evidence that alterations in the methylome in PD are discernible in blood, evolve over time, and reflect cellular processes linked to ongoing neurodegeneration. These findings lend support to the potential of blood DNA methylation as an epigenetic biomarker for PD. To fully comprehend DNA methylation changes throughout the progression of PD, additional profiling at longer intervals and during the prodromal stage will be necessary.