Phung Duong My, Lee Jinwoo, Hong SangKyoon, Kim Young Eun, Yoon Jeehee, Kim Yun Joong
Department of Biomedical Gerontology, Ilsong Institute of Life and Science, Hallym University, Anyang, South Korea.
Department of Computer Engineering, Hallym University, Chuncheon, South Korea.
Front Neurosci. 2020 Dec 18;14:596105. doi: 10.3389/fnins.2020.596105. eCollection 2020.
Studies regarding differentially expressed genes (DEGs) in Parkinson's disease (PD) have focused on common upstream regulators or dysregulated pathways or ontologies; however, the relationships between DEGs and disease-related or cell type-enriched genes have not been systematically studied. Meta-analysis of DEGs (meta-DEGs) are expected to overcome the limitations, such as replication failure and small sample size of previous studies.
Meta-DEGs were performed to investigate dysregulated genes enriched with neurodegenerative disorder causative or risk genes in a phenotype-specific manner.
Six microarray datasets from PD patients and controls, for which substantia nigra sample transcriptome data were available, were downloaded from the NINDS data repository. Meta-DEGs were performed using two methods, combining -values and combing effect size, and common DEGs were used for secondary analyses. Gene sets of cell type-enriched or disease-related genes for PD, Alzheimer's disease (AD), and hereditary progressive ataxia were constructed by curation of public databases and/or published literatures.
Our meta-analyses revealed 449 downregulated and 137 upregulated genes. Overrepresentation analyses with cell type-enriched genes were significant in neuron-enriched genes but not in astrocyte- or microglia-enriched genes. Meta-DEGs were significantly enriched in causative genes for hereditary disorders accompanying parkinsonism but not in genes associated with AD or hereditary progressive ataxia. Enrichment of PD-related genes was highly significant in downregulated DEGs but insignificant in upregulated genes.
Downregulated meta-DEGs were associated with PD-related genes, but not with other neurodegenerative disorder genes. These results highlight disease phenotype-specific changes in dysregulated genes in PD.
关于帕金森病（PD）中差异表达基因（DEG）的研究主要集中在常见的上游调节因子、失调的信号通路或本体论上；然而，DEG与疾病相关基因或细胞类型富集基因之间的关系尚未得到系统研究。DEG的荟萃分析（meta-DEG）有望克服以往研究中的局限性，如复制失败和样本量小等问题。
进行meta-DEG以研究以表型特异性方式富集神经退行性疾病致病基因或风险基因的失调基因。
从美国国立神经疾病与中风研究所（NINDS）数据存储库下载了六个来自PD患者和对照的微阵列数据集，这些数据集有黑质样本转录组数据。使用两种方法进行meta-DEG分析，即合并P值和合并效应大小，并将常见的DEG用于二次分析。通过整理公共数据库和/或已发表的文献，构建了PD、阿尔茨海默病（AD）和遗传性进行性共济失调的细胞类型富集基因或疾病相关基因集。
我们的荟萃分析揭示了449个下调基因和137个上调基因。对细胞类型富集基因的过度表达分析在神经元富集基因中具有显著性，但在星形胶质细胞或小胶质细胞富集基因中不具有显著性。meta-DEG在伴有帕金森综合征的遗传性疾病的致病基因中显著富集，但在与AD或遗传性进行性共济失调相关的基因中不显著。PD相关基因在下调的DEG中高度富集，但在上调基因中不显著。
下调的meta-DEG与PD相关基因有关，但与其他神经退行性疾病基因无关。这些结果突出了PD中失调基因的疾病表型特异性变化。
