Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

Abstract

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

“…Complementary results were found in the studies, since the first found no difference in global DNA methylation between the twins tested 47 , but disease-associated differences at specific CpG islands; the second found a DNA globally hypomethylated with regions of hypermethylation 48 . Both performed pathway enrichment analysis, revealing pathways related to brain development, axon guidance, cell adhesion, metabolism and long-term potentiation.…”

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

“…Genome-wide methylation differences have also been analyzed in blood (Dempster et al, 2011; Houtepen et al, 2016; Li et al, 2015; Sabunciyan et al, 2015; Walker et al, 2016) and in different post-mortem brain regions, such as the BA9 (Zhao et al, 2015), frontal cortex (Mill et al, 2008; Xiao et al, 2014), anterior cingulate (Xiao et al, 2014), and cerebellum (Chen et al, 2014) from BD patients and controls.…”

“…These mechanisms include the actions of microRNAs, long noncoding RNAs, and covalent modifications of histones and DNA, forming either repressive or permissive chromatin, thereby modulating gene expression (Breiling and Lyko, 2015; Kouzarides, 2007; Roundtree and He, 2015). DNA methylation is the most stable form of epigenetic alteration, and several studies suggested a critical role for this mechanism in BD (Li et al, 2015; Nestler et al, 2015). This paper aims to survey the literature to shed light on the potential role of DNA methylation in the pathophysiology and treatment of BD.…”

Transcriptome Analysis of Systems Biology for Schizophrenia

“…Although there are no speciic methylated gene paterns identiied in schizophrenia, there are signiicant associations between promoter CpG islands (CGI) hypermethylation with gene repression and CGI hypomethylation with increased gene expression [17]. CGIs have been suggested to suppress gene expression by blocking the promoters.…”