Characterization of baseline and longitudinal DNA Methylation in patients with sporadic Parkinson’s disease

Objective To characterize DNA methylation differences between sporadic Parkinson’s Disease and healthy control individuals enrolled in the Parkinson’s Progression Markers Initiative. Methods We 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 Parkinson’s Disease individuals and 86 healthy control individuals). DNA methylation data was collected at the time of enrollment and longitudinally over three years. Results This 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 Results Our study provides evidence that alterations in the methylome in Parkinson’s 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 Parkinson’s Disease. To fully comprehend DNA methylation changes throughout the progression of Parkinson’s Disease, additional profiling at longer intervals and during the prodromal stage will be necessary. ### Competing Interest Statement Dr. Paulina Gonzalez-Latapi is supported by an Early Investigator Career Award from the Michael J. Fox Foundation. ### Funding Statement This study was supported through an Early Investigator Career Award funded by the Michael J Fox Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data for this study was obtained from the Parkinson Progression Markers Initiative (PPMI). Data is openly available and can be accessed at: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author on reasonable request.