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 the 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 nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules 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 the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease, second in prevalence only to Alzheimer’s disease (Mayeux and Stern, 2012; Tysnes and Storstein, 2017)
The PD individuals were at an earlier stage [Hoehn and Yahr = 1.89 ± 0.48; UPDRS Part 3 = 13.9 ± 2.1] and were cognitively normal based on the Mini-mental Status Exam (MMSE) score of 29 or greater
In the DNA methylation data analysis, a rigorous quality control workflow was applied, with batch effects from methylation array position explicitly removed by ComBat (Johnson et al, 2007) and cell proportion adjusted for by using a reference database of DNAm profiles of the major cell types presented in whole blood, as implemented in RefbaseEWAS (Houseman et al, 2012)
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease, second in prevalence only to Alzheimer’s disease (Mayeux and Stern, 2012; Tysnes and Storstein, 2017). PD characteristically manifests as overt motor defects following the destruction of dopaminergic neurons in the substantia nigra and is pathologically associated with α-synuclein protein aggregation into intracellular cytoplasmic inclusions, termed Lewy bodies. This brain pathology may result from initial insults via olfaction or in the gut, with retrograde trafficking into the affected brain regions (Hawkes et al, 2009; Planken et al, 2017). A combination of multiple biomarker approaches as a diagnostic panel could accelerate improvements in early diagnostic accuracy This will be important in pushing the point at which diagnosis or high-risk prediction can be made to an even earlier time point in pre-motor prodromal stages. Multiple pre-motor biomarkers are actively being investigated for their potential to identify earlystage PD or patients at risk for developing PD (Haas et al, 2012), including clinical measures (rapid eye movement behavior disorder, olfactory deficits, mood disorders), molecular measures (α-syn in cerebrospinal fluid and blood), and brain imaging
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