Transcriptome Changes in Relation to Manic Episode

Abstract

Bipolar disorder (BD) is highly heritable and well known for its recurrent manic and depressive episodes. The present study focused on manic episode in BD patients and aimed to investigate state-specific transcriptome alterations between acute episode and remission, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and micro-RNAs (miRNAs), using microarray and RNA sequencing (RNA-Seq) platforms. BD patients were enrolled with clinical information, and peripheral blood samples collected at both acute and remission status spanning for at least 2 months were confirmed by follow-ups. Symptom severity was assessed by Young Mania Rating Scale. We enrolled six BD patients as the discovery samples and used the Affymetrix Human Transcriptome Array 2.0 to capture transcriptome data at the two time points. For replication, expression data from Gene Expression Omnibus that consisted of 11 BD patients were downloaded, and we performed a mega-analysis for microarray data of 17 patients. Moreover, we conducted RNA sequencing (RNA-Seq) in additional samples of 7 BD patients. To identify intraindividual differentially expressed genes (DEGs), we analyzed data using a linear model controlling for symptom severity. We found that noncoding genes were of majority among the top DEGs in microarray data. The expression fold change of coding genes among DEGs showed moderate to high correlations (∼0.5) across platforms. A number of lncRNAs and two miRNAs ( MIR181B1 and MIR103A1 ) exhibited high levels of gene expression in the manic state. For coding genes, we reported that the taste function-related genes, including TAS2R5 and TAS2R3 , may be mania state-specific markers. Additionally, four genes showed a nominal p -value of less than 0.05 in all our microarray data, mega-analysis, and RNA-Seq analysis. They were upregulated in the manic state and consisted of MS4A14 , PYHIN1 , UTRN , and DMXL2 , and their gene expression patterns were further validated by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). We also performed weight gene coexpression network analysis to identify gene modules for manic episode. Genes in the mania-related modules were different from the susceptible loci of BD obtained from genome-wide association studies, and biological pathways in relation to these modules were mainly related to immune function, especially cytokine–cytokine receptor interaction. Results of the present study elucidated potential molecular targets and genomic networks that are involved in manic episode. Future studies are needed to further validate these biomarkers for their roles in the etiology of bipolar illness.

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

“…65,[72][73][74] DNA methylation in promoters is typically associated with the repression of gene expression and may underlie at least some of the transcriptomic changes reported for BD in multiple tissues. [75][76][77][78][79] Moreover, several preclinical and clinical studies have shown that early-life traumatic experiences can induce stable methylation alterations that persist into adulthood, suggesting epigenetic-based alterations as mediators of the clinical effects of early adversity. [80][81][82] Interestingly, one of the mechanisms by which methylomes have been shown to interfere with BD phenotype is the modulation of biological aging processes.…”

PYHIN1 correlates with CD8+ T cells infiltration and confers good patient survival in oral cancer

“…In bipolar disorder, biological pathways in relation to PYHIN1 were mainly associated with immune function, especially cytokine–cytokine receptor interaction. 18 PYHIN1 was also regarded as an interferon pathway gene affecting mycobacterium tuberculosis infection and contributed to the induction of interferon response. 10 , 19 The dysregulation of PYHIN1 in pediatric inflammatory bowel disease also suggested the involvement of PYHIN1 in immune responses.…”

Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression

“…Another pathway significantly influenced by chronic lithium treatment in our animal mania model was bitter taste receptor pathway. Recent transcriptome study by Lee et al [ 25 ] showed altered taste receptors gene expression during manic episodes. These genes included bitter taste receptors, TAS2R5 and TAS2R3, that were suggested as potential markers specific for the manic state [ 25 ].…”

“…Recent transcriptome study by Lee et al [ 25 ] showed altered taste receptors gene expression during manic episodes. These genes included bitter taste receptors, TAS2R5 and TAS2R3, that were suggested as potential markers specific for the manic state [ 25 ]. These receptors were previously found downregulated (together with olfactory receptors) in the dorsolateral prefrontal cortex of schizophrenia postmortem brain tissues [ 26 ] and this downregulation influenced altered cognition.…”

“…The paper by ConLiGen showed significant associations for two long non-coding RNAs (lncRNAs) localized on chromosome 21 with lithium prophylactic efficacy supporting their involvement in modulating a clinical response [ 29 ]. Several studies reported that lncRNAs expression was dysregulated in psychiatric conditions, including BD [ 30 ] whereas Lee et al found recently that lncRNAs were the predominant category showing upregulation during an acute manic episode [ 25 ]. Here, we report for the first time that lncRNAs expression is altered by chronic lithium treatment and suggest they may be regulators of antimanic lithium action.…”