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Open AccessArticle

Coding and Non-Coding RNA Abnormalities in Bipolar Disorder

1
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
2
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht University, 3584 CX Utrecht, The Netherlands
3
GGNet Mental Health, 7328 JE Apeldoorn, The Netherlands
4
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht University, 3584 CX Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Genes 2019, 10(11), 946; https://doi.org/10.3390/genes10110946
Received: 17 September 2019 / Revised: 5 November 2019 / Accepted: 15 November 2019 / Published: 19 November 2019
(This article belongs to the Special Issue Genetics of Psychiatric Disorders)
The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. Twenty genes, some of which not previously implicated in BPD, were differentially expressed (DE). PCR validation and replication confirmed the implication of these DE genes. Functional in silico analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, an overall increased number of alternative splicing events in BPD was detected, as well as an increase in the number of genes carrying alternative splicing events. Finally, a large reservoir of circRNAs populating brain tissue not affected by BPD is described, while in BPD altered levels of two circular transcripts, cNEBL and cEPHA3, are reported. cEPHA3, hitherto unlinked to BPD, is implicated in developmental processes in the central nervous system. Although we did not perform replication analyses of non-coding RNA findings, our findings hint that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research. View Full-Text
Keywords: bipolar disorder; circular RNA; long non-coding RNA; alternative splicing; cEPHA3; histone H3-K4 demethylation; sequencing bipolar disorder; circular RNA; long non-coding RNA; alternative splicing; cEPHA3; histone H3-K4 demethylation; sequencing
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Luykx, J.J.; Giuliani, F.; Giuliani, G.; Veldink, J. Coding and Non-Coding RNA Abnormalities in Bipolar Disorder. Genes 2019, 10, 946.

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