Table 2.
Studies evaluating the association between RNA markers and bipolar disorder in cellular models.
| Ref. | Sample | RNA Source | RNA Type | Measurement Method | Targets | Main Findings |
|---|---|---|---|---|---|---|
| [52] | 3 patients with BD and 3 HCs | Neurons differentiated from iPSC-derived NPCs | mRNA, miRNA | Microarray, qPCR | Genome wide | Six (miR-128-3p, miR-138-2-3p, miR-195-5p, miR-382-5p, miR-487b-3p and miR-744-3p) and two miRNAs (miR-10b-5p and miR-10b-3p) showed higher or lower levels, respectively, in neurons derived from patients with BD compared with HCs |
| [50] | iPSC-derived NPCs from 1 patient with BD and 1 HC; post-mortem brain samples from 29 patients with BD and 34 HCs | NPCs, post-mortem brain samples | mRNA, miRNA | Nanostring, qPCR | miR-34a and predicted targets | Increased miR-34a levels in the cerebellum of patients with BD compared with HCs. In NPCs, the enhancement of miR-34a expression impaired neuronal differentiation, expression of synaptic proteins and neuronal morphology |
| [45] | 37 euthymic patients with BD I and 20 HCs | LCLs | mRNA | NGS, qPCR | 19 circadian genes | Lower levels of ARNTL and higher levels of CIART and BHLHE41 in patients with BD compared with HCs |
| [44] | 62 patients with BD I and 17 HCs | LCLs | mRNA | Microarray, qPCR | Genome wide | No significant difference between patients with BD and HCs |
| [53] | iPSC and NPCs from 6 patients with BD and 4 HCs; post-mortem brain samples from 35 patients with BD and 34 HCs (BA46), 15 patients with BD and 15 HCs (corpus callosum and BA8) | NPCs, iPSCs and post-mortem brain samples | mRNA, lncRNA | qPCR | BDNF and BDNF-AS | BDNF expression was lower in iPSCs but higher in NPCs from BD patients compared with HCs. BDNF expression was lower in BA46 but not in BA8 or corpus callosum from patients with BD compared with HCs |
| [51] | 8 patients with BD I and 8 HCs | Brain organoids generated from iPSCs | mRNA | NGS | Genome wide | Downregulation of pathways involved in cell adhesion, neurodevelopment and synaptic biology and upregulation of genes involved in immune signaling in organoids from patients with BD compared with HCs. The central hub in the network analysis was the neurocan gene, located in a locus with evidence for genome-wide significant association for BD |
| [54] | 4 patients with BD and 4 HCs | Neurons and NPCs derived from iPSCs | mRNA | Microarray, qPCR | Genome wide | 328 genes were differentially expressed neurons from patients with BD and HCs. These genes were enriched for alterations in RNA biosynthesis and metabolism, protein trafficking and receptor signaling pathways. Higher levels of GAD1 in neurons from patients with BD were confirmed with qPCR |
| [55] | 2 brothers with BD and 2 unaffected parents | NPCs derived from iPSCs | mRNA | Nanostring, NGS | Genome wide | NPCs expressing CXCR4 from both BD patients compared to their unaffected parents showed differences in the expression of genes critical for neuroplasticity, including Wnt pathway components and ion channel subunits |
| [56] | 2 monozygotic twins discordant for schizoaffective disorder, bipolar type, and 2 pairs of monozygotic twins discordant for SZ | Brain organoids generated from iPSCs | mRNA | scRNAseq | Genome wide | Enhanced GABAergic specification and reduced cell proliferation following diminished Wnt signaling in the patient with BD, which was confirmed in iPSC-derived forebrain neuronal cells |
| [47] | 9 patients with BD who died by suicide, 17 at low risk of suicide, 17 at high risk of suicide and 21 HCs | LCLs | mRNA | qPCR | SAT1 | In vitro treatment with LiCl 1 mM increased SAT1 expression in the high and low risk groups as well as in HCs, but not in suicide completers |
| [49] | 7 patients with BD who died by suicide, 11 patients at low risk of suicide and 12 HCs | LCLs, NPCs and post-mortem brain samples | miRNA | Nanostring, qPCR | Genome wide | Higher levels of miR-4286 and lower levels of miR-186-5p in LCLs from patients who died by suicide compared with patients at low risk of suicide and HCs. In vitro treatment with lithium reduced miR-4286 expression in human NPCs |
ARNTL1, basic helix–loop–helix ARNT-like 1; BD I, bipolar disorder type 1; BDNF, brain-derived neurotrophic factor; BHLHE41, basic helix–loop–helix family member E41; CIART, circadian-associated repressor of transcription; CXCR4, CXC chemokine receptor-4; GAD1, glutamate decarboxylase; HCs, healthy controls; iPSCs, induced pluripotent stem cells; lncRNA, long noncoding RNA; LCLs, lymphoblastoid cell lines; mRNA, messenger RNA; microRNA, miRNA; NGS, next-generation sequencing; NPCs, neural precursor cells; qPCR, quantitative PCR; SAT1, spermidine/spermine N1-acetyltransferase; scRNAseq, single cell RNA sequencing.