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

ObjectiveTo characterize DNA methylation differences between sporadic Parkinsons Disease and healthy control individuals enrolled in the Parkinsons Progression Markers Initiative. MethodsWe characterized cross-sectional and longitudinal DNA methylation differences between individuals with sporadic (i.e., non-genetic) PD and healthy controls. We included 282 individuals (196 Parkinsons Disease individuals and 86 healthy control individuals). DNA methylation data was collected at the time of enrollment and longitudinally over three years. ResultsThis analysis revealed 81,604 differentially methylated positions and 5,281 differentially methylated regions between sporadic PD and healthy controls. Gene ontology analysis revealed that these differentially methylated positions and regions 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. Interpretation of ResultsOur study provides evidence that alterations in the methylome in Parkinsons Disease 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 Parkinsons Disease. To fully comprehend DNA methylation changes throughout the progression of Parkinsons Disease, additional profiling at longer intervals and during the prodromal stage will be necessary.