Young Juan I, Sivasankaran Sathesh K, Wang Lily, Ali Aleena, Mehta Arpit, Davis David A, Dykxhoorn Derek M, Petito Carol K, Beecham Gary W, Martin Eden R, Mash Deborah C, Pericak-Vance Margaret, Scott William K, Montine Thomas J, Vance Jeffery M
John 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.
Neurol Genet. 2019 Jun 24;5(4):e342. doi: 10.1212/NXG.0000000000000342. eCollection 2019 Aug.
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.
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.
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 < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01).
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.
鉴于已知DNA甲基化与环境暴露之间存在密切关系，我们研究了帕金森病（PD）中受影响的脑区在PD病例和对照之间是否存在差异甲基化。
使用DNA芯片阵列对根据Beecham等人的标准选择的病理确诊的PD病例和对照的迷走神经背运动核（DMV）、黑质（SN）和扣带回（CG）进行全基因组DNA甲基化筛查。分析检查了每个脑区病例和对照之间的差异甲基化区域（DMR）。还对每个脑区进行了RNA测序和通路分析。
分析纳入了38例PD病例和41例对照。甲基化研究显示，病例和对照之间，DMV中有234个显著的DMR，SN中有44个，CG中有141个（Sidak < 0.05）。对这些基因的通路分析显示Wnt信号通路显著富集（FDR < 0.01）。
我们的数据表明，PD病例和对照之间存在显著的DNA甲基化变化，尤其是在DMV，这是PD中最早受影响的区域之一。这些甲基化变化的病因尚不清楚，但DMV中发生的甲基化变化占主导地位支持了这样的假设，即迷走神经功能，可能涉及胃肠道系统，在PD发病机制中很重要。这些数据还独立支持参与Wnt信号传导的基因可能是PD神经退行性过程中的一个因素。
