Integrative In Silico Analysis of Genome-Wide DNA Methylation Profiles in Schizophrenia
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Integrative In Silico Analysis of Genome-Wide DNA Methylation Profiles in Schizophrenia Diego A. Forero 1
&
Yeimy González-Giraldo 2
Received: 6 January 2020 / Accepted: 13 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Schizophrenia (SZ) is a complex and severe psychiatric disorder, which has a global lifetime prevalence of 0.4% and a heritability of around 0.81. A number of epigenome-wide association studies (EWAS) have been carried out for SZ, with discordant results. The main aim of this study was to carry out an integrative in silico analysis of available genome-wide DNA methylation profiles in schizophrenia. In this work, an integration of multiple lines of evidence (top candidate genes from several EWAS and genomewide expression and association data) was carried out, in order to identify top differentially methylated (DM) genes for SZ. In addition, functional enrichment and protein-protein interaction analyses were carried out. Several top differentially methylated genes, such as APC, CACNB2, and PRKN, were found, and an enrichment of binding sites for brain-expressed transcription factors, such as FOXO1, MYB, and ZIC3, was also observed. Moreover, a protein-protein interaction network showed a central role for DISC1 and ZNF688 genes, and experimentally validated targets of MIR-137, such as and KCNB2, NRXN1, and SYN2, were identified among DM genes. This is the first integrative in silico analysis of available genome-wide DNA methylation profiles in schizophrenia. This work identified novel candidate genes and pathways for SZ and provides the basis to explore their role in the pathogenesis of SZ in future studies. Keywords Epigenomics . DNA methylation . Psychiatric genomics . Computational biology . Schizophrenia
Introduction Schizophrenia (SZ) is a complex and severe psychiatric disorder, clinically characterized by psychotic symptoms (such as delusions and auditory hallucinations), among others (Lieberman and First 2018). It has been found that SZ has a median global lifetime prevalence of 0.4% (Saha et al. 2005), and a meta-analysis of twin studies estimated the heritability for SZ around 0.81 (confidence interval, 0.73–0.90) (Sullivan et al. 2003). Genome-wide association studies (GWAS) for SZ have identified robust association signals with singleElectronic supplementary material The online version of this article (https://doi.org/10.1007/s12031-020-01585-w) contains supplementary material, which is available to authorized users. * Diego A. Forero [email protected] 1
School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá, Colombia
2
Center for Psychosocial Studies for Latin America and the Caribbean, School of Psychosocial Therapies, Universidad Antonio Nariño, Bogotá, Colombia
nucleotide polymorphisms (SNPs) in the major histocompatibility complex and MIR-137 (a brain-expressed miRNA) genomic regions, among others (Modai and Shomron 2016). Alterations in epigenetic factors have been recently explored as possible pat
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