RNA Sequencing in Bipolar Disorder: From Long Non-coding to Circular rnas

Abstract

Bipolar disorder (BPD) is a highly debilitating psychiatric disorder. The underlying molecular mechanisms of BPD remain largely unknown. Studies targeting postmortem brain tissues of BPD patients have identified very few consistently replicated differences in the expression levels of protein-coding RNAs across different areas of the brain. Since differential expression of the human genome produces a wide spectrum of protein-coding and noncoding RNAs, we hypothesized that major molecular deficits associated with BPD could reflect dysregulation of multiple classes of RNA. To test this hypothesis, we obtained postmortem human medial frontal gyrus tissue from BPD patients and healthy controls (n = 16). To survey the implication of both protein-coding and long non-coding RNAs (lncRNAs) in BPD, we then performed RNA sequencing, PCR validation and replication experiments adopting a case-control design. Thirty-six genes and fifteen lncRNA transcripts not previously implicated in BPD were detected as differentially expressed (FDR < 0.1). Functional analyses identified enrichments of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, we report extensive alternative splicing defects in the brains of BPD subjects compared to controls. Finally, we describe for the first time a large reservoir of circular RNAs (circRNAs) that populate the medial frontal gyrus and report significantly altered levels of two circular transcripts (cNEBL and cEPHA3) from the NEBL and EPHA3 loci in BPD. Our findings may not only contribute to gain insight into the pathophysiology of BPD but may be tested in the near future as potential biomarkers for diagnostics.

Disclosure of interest

The authors have not supplied their declaration of competing interest.