Meta-Analysis of Differentially Expressed Genes in the Substantia Nigra in Parkinson's Disease Supports Phenotype-Specific Transcriptome Changes

Duong My Phung; Jinwoo Lee; SangKyoon Hong; Young Eun Kim; Jeehee Yoon; Yun Joong Kim

doi:10.3389/fnins.2020.596105

Meta-Analysis of Differentially Expressed Genes in the Substantia Nigra in Parkinson's Disease Supports Phenotype-Specific Transcriptome Changes

Front Neurosci. 2020 Dec 18:14:596105. doi: 10.3389/fnins.2020.596105. eCollection 2020.

Authors

Duong My Phung¹, Jinwoo Lee², SangKyoon Hong³, Young Eun Kim⁴, Jeehee Yoon², Yun Joong Kim^{5

6}

Affiliations

¹ Department of Biomedical Gerontology, Ilsong Institute of Life and Science, Hallym University, Anyang, South Korea.
² Department of Computer Engineering, Hallym University, Chuncheon, South Korea.
³ Hallym Institute of Translational Genomics and Bioinformatics, Anyang, South Korea.
⁴ Laboratory of Parkinson's Disease and Neurogenetics, Department of Neurology, Hallym University, Anyang, South Korea.
⁵ Department of Neurology, Yonsei University College of Medicine, Yongin, South Korea.
⁶ Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea.

Abstract

Background: 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.

Purpose: Meta-DEGs were performed to investigate dysregulated genes enriched with neurodegenerative disorder causative or risk genes in a phenotype-specific manner.

Methods: 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 p-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.

Results: 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.

Conclusion: 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.

Keywords: Parkinson’s disease; differentially expressed genes; disease-related genes; meta-analysis; substantia nigra.