Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease.
Author: Young JI1, Sivasankaran SK1, Wang L1, Ali A1, Mehta A1, Davis DA1, Dykxhoorn DM1, Petito CK1, Beecham GW1, Martin ER1, Mash DC1, Pericak-Vance M1, Scott WK1, Montine TJ1, Vance JM1
Affiliation:
1John P. Hussman Institute for Human Genomics (J.I.Y., S.K.S., A.A., A.M., D.M.D., G.W.B., E.R.M., M.P.-V., W.K.S., J.M.V.), Miller School of Medicine, University of Miami; Department of Public Health Sciences (L.W.), Division of Biostatistics, Miller School of Medicine, University of Miami; Department of Neurology (D.A.D., D.C.M.), Miller School of Medicine, University of Miami; Department of Pathology (C.K.P.), Miller School of Medicine, University of Miami, FL; and Department of Pathology (T.J.M.), Stanford University, CA.
Conference/Journal: Neurol Genet.
Date published: 2019 Jun 24
Other:
Volume ID: 5 , Issue ID: 4 , Pages: e342 , Special Notes: doi: 10.1212/NXG.0000000000000342. eCollection 2019 Aug. , Word Count: 241
Objective: Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls.
Methods: DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area.
Results: Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak p < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01).
Conclusions: Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.
PMID: 31403079 PMCID: PMC6659138 DOI: 10.1212/NXG.0000000000000342
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