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DNA methylation and expression profiles of whole blood in Parkinson’s disease (Methylation)

ABSTRACT: Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor NFYA, receptor tyrosine kinase DDR1, ubiquitin ligase RNF5, acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation (eQTM) sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57, among others. Functional epigenetic modules (FEM) were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support characterization of larger sample cohorts, with the goal of building a thorough, accurate and non-invasive molecular PD biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165081 | GEO | 2021/03/11

REPOSITORIES: GEO

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Project description:Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD. We study changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls (Discovery set?) by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. By applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays, gene expression profiling discriminates patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts were validated by RT-qPCR in an independent cohort of 12 patients and controls (?Validation set). Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention. Analyzed samples include blood samples from 40 PD patients and 20 healthy controls. Of the original 60 samples, one (a control sample) did not pass the microarray hybridization quality controls and was excluded from further analyses. All results of bioinformatics analyses shown in this study refer to this set of 59 samples (reported here).

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DNA methylation and expression profiles of whole blood in Parkinson’s disease (Methylation)

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