Table 1.
Studies evaluating the association between RNA markers and bipolar disorder in biofluids or peripheral cells.
| Ref. | Sample | RNA Source | RNA Type | Method | Targets | Main Findings |
|---|---|---|---|---|---|---|
| [28] | 15 patients with BD and 17 with MDD during a depression episode and at remission | Whole blood | miRNA | qPCR | miR-499, miR-798 and miR-1908 | Lower levels of all miRNAs in the depressive state compared with remission exclusively in patients with BD |
| [27] | 58 patients with BD I (19 manic and 39 euthymic) and 51 HCs | Whole blood | miRNA | qPCR | miR-26b-5p, miR-9-5p, miR-29a-3p, miR-106a-5p, miR-106b-5p, miR-107, miR-125a-3p and miR-125b-5p | Levels of miR-29a-3p, miR-106b-5p, miR-107 and miR-125a-3p were significantly higher in patients with BD compared with HCs. Levels of miR-106a-5p and miR-107 were significantly higher in manic patients compared to euthymic patients |
| [25] | 69 patients with BD (15 depressed, 27 manic and 27 euthymic) and 41 HCs | Plasma exosomes | miRNA | qPCR | Genome wide | Levels of miR-484, miR-652-3p and miR-142-3p were lower, while levels of miR-185-5p were higher in patients with BD compared with HCs. No alterations among different states of BD |
| [20] | Discovery cohort: 7 patients with BD, 7 with MDD and 6 HCs; validation cohort: 27 patients with BD and 32 with MDD | Plasma | miRNA | Microarray, qPCR | Genome wide | Higher levels of miR-19b-3p in patients with BD compared with patients with MDD |
| [33] | 54 patients with BD I, 45 with BD II and 42 HCs | PBMC | mRNA | qPCR | COMT, DNMT, GAD67, MECP2, PDYN and SERT | Lower PDYN expression in patients with BD II but not BD I compared with HCs. Higher levels of genes involved in methylation, such as DNMT3b and MECP2, in patients with BD II compared with HCs |
| [34] | 169 patients with BD and 211 HCs | Whole blood | mRNA | qPCR | NOTCH4 | Higher NOTCH4 levels in patients with BD compared with HC |
| [18] | 50 patients with BD I and 50 HCs | Whole blood | mRNA, lncRNA | qPCR | SNHG6, MALAT1, Linc00511, Linc00346, VDR and CYP27B1 | Levels of VDR, SNHG6, CYP27B1, MALAT1 and Linc00346 were higher in patients compared with HCs |
| [24] | 20 patients with BD I and 21 HCs | Plasma EV | miRNA | Microarray | Genome wide | 33 nominally significant microRNAs altered in patients with BD |
| [17] | Discovery cohort: 4 patients with BD and 4 HCs; validation cohort: 16 patients with BD and 16 controls | Whole blood | mRNA, circRNA | NGS and qPCR | Genome wide | 50 circRNAs and 244 mRNAs showed nominally significant higher levels, while 44 circRNAs and 294 mRNAs lower levels in patients with BD compared with HCs |
| [16] | Discovery cohort: 18 patients with BD, 44 with MDD, and 31 HCs; validation cohort: 26 patients with BD, 84 with MDD and 74 HCs | Plasma | mRNA, miRNA | NGS and qPCR | Genome wide | Higher levels of hsa-let-7e-5p and hsa-miR-125a-5p in patients with either BD or MDD compared with HCs |
| [19] | Discovery cohort: 4 patients with BD and 4 HCs; validation cohort: 130 patients with BD and 116 HCs | Whole blood | mRNA, lncRNA | NGS and qPCR | Genome wide | Higher levels of the NR_028138.1 lncRNA in patients with BD compared with HCs |
| [21] | Discovery cohort: 3 patients with BD II and 3 HCs; validation cohort: 99 patients with BD II and 115 HCs | Serum | miRNA | NGS and qPCR | Genome wide | Levels of miR-7-5p, miR-23b-3p, miR-142-3p, miR-221-5p and miR-370-3p were higher in patients with BD II compared with HCs |
| [32] | 51 patients with BD and 116 HCs | White blood | mRNA | qPCR | COMT, GCAT, NRG1, PSAT1, SHMT2, SLC1A4 and SRR | A logistic ridge regression model including age, gender and mRNA expression levels of the 7 NMDAR genes showed an AUC of 0.92 in differentiating patients with BD from HCs |
| [29] | 20 patients with BD, 20 with MDD and 20 HCs | Whole blood | miRNA | Microarray and qPCR | Genome wide | 5 miRNAs showed higher levels specifically in patients with BD compared with HCs (hsa-miR-140-3p, hsa-miR-30d-5p, hsa-miR-330-5p, hsa-miR-378a-5p and hsa-miR-21-3p), while hsa-miR-330-3p and hsa-miR-345-5p showed higher levels in both BD and MDD |
| [30] | 19 patients with BD, 20 with SZ and 20 HCs | PBMC | circRNA | NGS and qPCR | Genome wide | Levels of 30 circRNAs were specifically altered in patients with BD compared with HCs |
| [35] | 50 patients with BD and 50 HCs | PBMC | lncRNA | qPCR | 3 lncRNAs related to oxidative stress (lincRNA-p21, lincRNA-ROR and lincRNA-PINT) | Levels of all lncRNAs were lower in patients with BD, and specifically in male patients with BD, compared with HCs |
| [36] | 50 patients with BD and 50 HCs | PBMC | lncRNA | qPCR | 5 lncRNAs related to oxidative stress (H19, LUCAT1, RMST, MEG3 and MT1DP) | Levels of LUCAT1, RMST and MEG3 were lower in patients with BD, specifically in male patients with BD, compared with HCs |
| [37] | 63 patients with BD, 42 with MDD and 55 HCs | PBMC | miRNA | qPCR | miR-499-5p | Higher levels of miR-499-5p in patients with BD (regardless of disease phase) compared with HCs |
| [22] | Serum: 41 patients with BD, 43 with MDD and 93 HCs; fibroblasts: 12 patients with BD, 23 with MDD and 15 HCs | Serum and fibroblasts | mRNA | qPCR | IGFBP2 | Lower IGFBP2 levels exclusively in patients with BD compared with HCs |
| [38] | 37 rapid cycling patients with BD in different affective states and 40 HCs | PBMC | mRNA | qPCR | 19 candidate genes | Lower levels of POLG and OGG1 in patients with BD compared with HCs; higher levels of NDUFV2 in patients in a depressed state compared with those in an euthymic state. A gene expression score including all genes showed an AUC of 0.73 in separating patients from HCs |
| [39] | 50 patients with BD and 50 HCs | PBMC | lncRNA | qPCR | DISC1 and DISC2 | Lower levels of DISC1 and higher levels of DISC2 in patients with BD compared with HCs (AUC: 0.76 and 0.68, respectively) |
| [40] | 50 patients with BD and 50 HCs | PBMC | lncRNA | qPCR | 6 apoptosis-related lncRNAs (CCAT2, TUG1, PANDA, NEAT1, FAS-AS1 and OIP5-AS1) | Levels of CCAT2, TUG1 and PANDA were higher and levels of OIP5-AS1 were lower in patients with BD patients compared with HCs. CCAT2 and TUG1 expression levels were only different in male subgroups |
| [23] | 11 drug-free manic psychotic patients with BD and 9 HCs | Plasma | miRNA | Nanostring and qPCR | Genome wide | Higher levels of hsa-miR-25-3p and hsa-miR-144-3p, and lower levels of hsa-miR-6721-5p in patients with BD compared with HCs |
| [41] | 66 patients with BD and 66 HCs | Plasma | miRNA | qPCR | 15 miRNAs | A model including levels of miR-15b-5p, miR-155-5p, miR-134-5p and miR-652-3p showing a 83.3% sensitivity and 78.8% specificity |
| [42] | 56 patients with BD I and 52 HCs | Whole blood | miRNA | qPCR | hsa-miR-145-5p, hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p and hsa-miR-4725 | Higher levels of hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p and lower levels of hsa-miR-145-5p in patients with BD compared with HCs |
| [43] | 50 patients with BD and 50 HCs | Whole blood | lncRNA | qPCR | Five NF-κB-associated lncRNAs (ANRIL, CEBPA-DT, H19, NKILA and HNF1A-AS1) | Lower levels of ANRIL, CEBPA-DT and HNF1-AS1 and higher levels of NKILA in patients with BD compared with HC. HFN1A-AS1 showed the best diagnostic parameters (AUC: 0.86). |
ANRIL, CDKN2B antisense RNA 1; AUC, area under the curve; BD I, bipolar disorder type 1; BD II, bipolar disorder type II; CCAT2, colon-cancer-associated transcript 2; CEBPA-DT, CEBPA-divergent transcript; COMT, catechol-O-methyltransferase; CYP27B1, cytochrome P450 family 27 subfamily B member 1; DISC1, DISC1 scaffold protein; DISC2, DISC2 scaffold protein; DNMTs, DNA methyltransferases; GAD67, glutamate decarboxylase; EVs, extracellular vesicles; FAT-AS1, FAS antisense RNA 1; GCAT, glycine C-acetyltransferase; H19, H19-imprinted maternally expressed transcript; HNF1A-AS1, HNF1A antisense RNA 1; IGFBP2, insulin-like growth factor-binding protein 2; LUCAT1, lung cancer-associated transcript 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MDD, major depressive disorder; MECP2, methyl CpG-binding protein 2; MEG3, maternally expressed 3; MT1DP, metallothionein 1D, pseudogene; NDUFV2, NADH:Ubiquinone oxidoreductase core subunit V2; NGS, next-generation sequencing; NEAT1, nuclear paraspeckle assembly transcript 1; NMDAR, N-methyl-D-aspartate receptor; NKILA, NF-KappaB interacting LncRNA; NOTCH4, notch receptor 4; NRG1, neuregulin 1; OGG1, 8-oxoguanine DNA glycosylase; OIP5-AS1, OIP5 antisense RNA 1; PANDA, ATPase copper transporting beta; PBMC, peripheral blood mononuclear cells; PDYN, prodynorphin; POLG, DNA Polymerase Gamma, Catalytic Subunit; PSAT1, phosphoserine aminotransferase 1; qPCR, quantitative PCR; RMST, rhabdomyosarcoma 2-associated transcript; SERT, serotonin transporter; SHMT2, serine hydroxymethyltransferase 2; SNHG6, small nucleolar RNA host gene 6; SLC1A4, solute carrier family 1 member 4; SRR, serine racemase; TUG1, taurine upregulated 1; VDR, vitamin D receptor.