Chuang Yu-Hsuan, Paul Kimberly C, Bronstein Jeff M, Bordelon Yvette, Horvath Steve, Ritz Beate
Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, 650 Charles E. Young Drive, Box 951772, Los Angeles, CA, 90095-1772, USA.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Genome Med. 2017 Aug 30;9(1):76. doi: 10.1186/s13073-017-0466-5.
Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways.
In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA).
Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10 and cg04772575 in ABCB9 p = 4.3 × 10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling.
This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.
几篇文章表明血液中的DNA甲基化水平与帕金森病（PD）有关，但需要一项涉及合适的基于人群的对照的大规模研究。本研究的目的是：（1）研究PD状态是否与血液/唾液中的DNA甲基化水平相关；（2）研究观察到的关联是否与血细胞类型有关；（3）根据生物学途径对全基因组显著标记（“CpG”）和CpG簇（共甲基化模块）进行特征描述。
在一项基于人群的PD病例对照研究中，我们研究了335例PD患者和237例对照的血液样本，以及另外128例患者和131例对照的唾液样本。使用Illumina Infinium阵列从超过486,000个CpG生成DNA甲基化数据。我们使用加权相关网络分析（WGCNA）识别CpG模块（簇）。
我们对血液的横断面分析确定了82个全基因组显著的CpG（包括LARS2中的cg02489202，p = 8.3×10；ABCB9中的cg04772575，p = 4.3×10）。血液中六个与PD相关的共甲基化模块中有三个显著富集了免疫系统相关基因。我们对唾液的分析确定了五个显著的CpG。与PD相关的CpG位于与线粒体功能、神经元投射、细胞骨架组织、全身免疫反应和铁处理相关的基因附近。
本研究表明：（1）PD状态与血液和唾液中的DNA甲基化水平有密切关联；（2）最显著的与PD相关的变化反映了血细胞组成的变化。总体而言，本研究突出了免疫系统在PD病因学中的作用，但未来的研究需要解决这些关系的因果结构。
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