Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

Sheng-Yu Lee, Ru-Band Lu, Liang-Jen Wang, Cheng-Ho Chang, Ti Lu, Tzu-Yun Wang, Kuo-Wang Tsai, Sheng-Yu Lee, Ru-Band Lu, Liang-Jen Wang, Cheng-Ho Chang, Ti Lu, Tzu-Yun Wang, Kuo-Wang Tsai

Abstract

The diagnosis of Bipolar II disorder (BD-II) is currently based on the patients' description of symptoms and clinical behavioral observations. This study explored the possibility of miRNA in peripheral blood (serum) as a specific biomarker for BD-II. We identified 6 candidate miRNAs to differentiate BD-II patients from controls using next-generation sequencing. We then examined these candidate miRNAs using real-time PCR in the first cohort (as training group) of 79 BD-II and 95 controls. A diagnostic model was built based on these candidate miRNAs and then tested on an individual testing group (BD-II: n = 20, controls: n = 20). We found that serum expression levels of miR-7-5p, miR-23b-3p, miR-142-3p, miR-221-5p, and miR-370-3p significantly increased in BD-II compared with controls in the first cohort, whereas that of miR-145-5p showed no significant difference. The diagnostic power of the identified miRNAs was further analyzed using receiver-operating characteristic (ROC). Support vector machine (SVM) measurements revealed that a combination of the significant miRNAs reached good diagnostic accuracy (AUC: 0.907). We further examined an independent testing group and the diagnostic power reached fair for BD-II (specificity = 90%, sensitivity = 85%). We constructed miRNA panels using SVM model, which may aid in the diagnosis for BD-II.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
(a) Flowchart to identify differentially expressed miRNA candidates through next-generation sequencing (b) Flowchart to evaluate the potential of miRNA candidates for diagnostic biomarker.
Figure 2
Figure 2
(A–F) The expression levels of circulating miRNAs in BD-II samples (n = 3) compared with controls (n = 3). (A) miR-7-5p (B) miR-23b-3p (C) miR-142-3p (D) miR-221-5p (E) miR-370-3p (F) miR-145-5p.
Figure 3
Figure 3
(A–F) Expression levels of circulating miRNAs in serum in BD-II and healthy controls (Training set). (A) miR-7-5p (B) miR-23b-3p (C) miR-142-3p (D) miR-221-5p (E) miR-370-3p (F) miR-145-5p. (Differences in the expression levels of miRNAs between patients and controls were compared using the t-test).
Figure 4
Figure 4
(A–F) Diagnostic power of the six miRNA candidates using receiver-operating characteristic (ROC) curve analysis. (A) miR-7-5p (B) miR-23b-3p (C) miR-142-3p (D) miR-221-5p (E) miR-370-3p (F) miR-145-5p. (The optimal diagnostic point was assessed at cutoff values with largest Youden’s index (sensitivity and specificity − 1)).
Figure 5
Figure 5
Diagnostic model of BD-II using support vector machine (SVM) (using expression of miRNA miR-7-5p + miR-142-3p + miR-221-5p + miR-370-3p from this first cohort as a training set).

References

    1. Angst J, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. Journal of affective disorders. 2003;73:133–146. doi: 10.1016/s0165-0327(02)00322-1.
    1. Benazzi, F. & Akiskal, H. S. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. Journal of affective disorders73, 33–38, S0165032702003270 (2003).
    1. Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV. The Psychiatric clinics of North America. 1999;22:517–534, vii. doi: 10.1016/s0193-953x(05)70093-9.
    1. Angst J. The bipolar spectrum. The British journal of psychiatry: the journal of mental science. 2007;190:189–191. doi: 10.1192/bjp.bp.106.030957.
    1. Ghaemi SN, Boiman E, Goodwin FK. Insight and outcome in bipolar, unipolar, and anxiety disorders. Comprehensive psychiatry. 2000;41:167–171. doi: 10.1016/S0010-440X(00)90043-9.
    1. Ghaemi SN, Soldani F, Hsu DJ. Evidence-based pharmacotherapy of bipolar disorder. The international journal of neuropsychopharmacology/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum. 2003;6:303–308. doi: 10.1017/S1461145703003626.
    1. MacQueen GM, Young LT. Bipolar II disorder: symptoms, course, and response to treatment. Psychiatr Serv. 2001;52:358–361. doi: 10.1176/appi.ps.52.3.358.
    1. Cheng LC, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature neuroscience. 2009;12:399–408. doi: 10.1038/nn.2294.
    1. Liu C, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell stem cell. 2010;6:433–444. doi: 10.1016/j.stem.2010.02.017.
    1. Tan L, et al. Circulating miR-125b as a biomarker of Alzheimer’s disease. Journal of the neurological sciences. 2014;336:52–56. doi: 10.1016/j.jns.2013.10.002.
    1. Fan HM, et al. Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients. Journal of psychiatric research. 2014;59:45–52. doi: 10.1016/j.jpsychires.2014.08.007.
    1. Song HT, et al. A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. Journal of psychiatric research. 2014;54:134–140. doi: 10.1016/j.jpsychires.2014.03.008.
    1. Bocchio-Chiavetto L, et al. Blood microRNA changes in depressed patients during antidepressant treatment. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. 2013;23:602–611. doi: 10.1016/j.euroneuro.2012.06.013.
    1. Ha TY. The Role of MicroRNAs in Regulatory T Cells and in the Immune Response. Immune network. 2011;11:11–41. doi: 10.4110/in.2011.11.1.11.
    1. Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM. Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biological psychiatry. 2011;69:188–193. doi: 10.1016/j.biopsych.2010.09.039.
    1. Wang Z, et al. MiRNA-206 and BDNF genes interacted in bipolar I disorder. Journal of affective disorders. 2014;162:116–119. doi: 10.1016/j.jad.2014.03.047.
    1. Yuan H, Mischoulon D, Fava M, Otto MW. Circulating microRNAs as biomarkers for depression: Many candidates, few finalists. Journal of affective disorders. 2018;233:68–78. doi: 10.1016/j.jad.2017.06.058.
    1. Menezes IC, von Werne Baes C, Lacchini R, Juruena MF. Genetic biomarkers for differential diagnosis of major depressive disorder and bipolar disorder: A systematic and critical review. Behav Brain Res. 2019;357-358:29–38. doi: 10.1016/j.bbr.2018.01.008.
    1. Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Archives of general psychiatry. 1978;35:837–844. doi: 10.1001/archpsyc.1978.01770310043002.
    1. Akiskal HS, Djenderedjian AM, Rosenthal RH, Khani MK. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry. 1977;134:1227–1233. doi: 10.1176/ajp.134.11.1227.
    1. Akiskal HS, et al. Differentiation of primary affective illness from situational, symptomatic, and secondary depressions. Archives of general psychiatry. 1979;36:635–643. doi: 10.1001/archpsyc.1979.01780060025002.
    1. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. Journal of affective disorders. 1998;50:143–151. doi: 10.1016/s0165-0327(98)00142-6.
    1. Angst J, Gamma A, Sellaro R, Lavori PW, Zhang H. Recurrence of bipolar disorders and major depression. A life-long perspective. Eur Arch Psychiatry Clin Neurosci. 2003;253:236–240. doi: 10.1007/s00406-003-0437-2.
    1. Benazzi F. Is 4 days the minimum duration of hypomania in bipolar II disorder? Eur Arch Psychiatry Clin Neurosci. 2001;251:32–34. doi: 10.1007/s004060170065.
    1. Judd Lewis L., Akiskal Hagop S., Schettler Pamela J., Coryell William, Maser Jack, Rice John A., Solomon David A., Keller Martin B. The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders? Journal of Affective Disorders. 2003;73(1-2):19–32. doi: 10.1016/S0165-0327(02)00324-5.
    1. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. doi: 10.1192/bjp.133.5.429.
    1. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62. doi: 10.1136/jnnp.23.1.56.
    1. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278–296. doi: 10.1111/j.2044-8260.1967.tb00530.x.
    1. Tseng Hui-Wen, Li Sung-Chou, Tsai Kuo-Wang. Metformin Treatment Suppresses Melanoma Cell Growth and Motility Through Modulation of microRNA Expression. Cancers. 2019;11(2):209. doi: 10.3390/cancers11020209.
    1. Zhou N, et al. MiR-7 inhibited peripheral nerve injury repair by affecting neural stem cells migration and proliferation through cdc42. Mol Pain. 2018;14:1744806918766793. doi: 10.1177/1744806918766793.
    1. Pogue AI, Lukiw WJ. Up-regulated Pro-inflammatory MicroRNAs (miRNAs) in Alzheimer’s disease (AD) and Age-Related Macular Degeneration (AMD) Cell Mol Neurobiol. 2018;38:1021–1031. doi: 10.1007/s10571-017-0572-3.
    1. Li B, Jiang Y, Xu Y, Li Y, Li B. Identification of miRNA-7 as a regulator of brain-derived neurotrophic factor/alpha-synuclein axis in atrazine-induced Parkinson’s disease by peripheral blood and brain microRNA profiling. Chemosphere. 2019;233:542–548. doi: 10.1016/j.chemosphere.2019.05.064.
    1. Lu X, et al. miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates. Cell Res. 2013;23:1356–1368. doi: 10.1038/cr.2013.145.
    1. Qing, X. et al. Mir-142-3p Regulates Inflammatory Response by Contributing to Increased TNF-alpha in Chronic Rhinosinusitis With Nasal Polyposis. Ear Nose Throat J, 145561319847972, 10.1177/0145561319847972 (2019).
    1. Mandolesi G, et al. miR-142-3p Is a Key Regulator of IL-1beta-Dependent Synaptopathy in Neuroinflammation. J Neurosci. 2017;37:546–561. doi: 10.1523/JNEUROSCI.0851-16.2016.
    1. Shende VR, Neuendorff N, Earnest DJ. Role of miR-142-3p in the post-transcriptional regulation of the clock gene Bmal1 in the mouse SCN. PLoS One. 2013;8:e65300. doi: 10.1371/journal.pone.0065300.
    1. Karadag M, et al. Chronotypical characteristics and related miR-142-3p levels of children with attention deficit and hyperactivity disorder. Psychiatry Res. 2019;273:235–239. doi: 10.1016/j.psychres.2018.12.175.
    1. Yilmaz SG, Isbir S, Kunt AT, Isbir T. Circulating microRNAs as Novel Biomarkers for Atherosclerosis. In Vivo. 2018;32:561–565. doi: 10.21873/invivo.11276.
    1. Zhou M, et al. Abnormal Expression of MicroRNAs Induced by Chronic Unpredictable Mild Stress in Rat Hippocampal Tissues. Mol Neurobiol. 2018;55:917–935. doi: 10.1007/s12035-016-0365-6.
    1. Kou CH, Zhou T, Han XL, Zhuang HJ, Qian HX. Downregulation of mir-23b in plasma is associated with poor prognosis in patients with colorectal cancer. Oncol Lett. 2016;12:4838–4844. doi: 10.3892/ol.2016.5265.
    1. Zhang Y, et al. miR-23b Suppresses Leukocyte Migration and Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting CCL7. Mol Ther. 2018;26:582–592. doi: 10.1016/j.ymthe.2017.11.013.
    1. Zhu Y, Wang JL, He ZY, Jin F, Tang L. Association of Altered Serum MicroRNAs with Perihematomal Edema after Acute Intracerebral Hemorrhage. PLoS One. 2015;10:e0133783. doi: 10.1371/journal.pone.0133783.
    1. Hu L, et al. MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase. Int Immunopharmacol. 2019;76:105887. doi: 10.1016/j.intimp.2019.105887.
    1. Gawryluk JW, Young LT. Signal transduction pathways in the pathophysiology of bipolar disorder. Curr Top Behav Neurosci. 2011;5:139–165. doi: 10.1007/7854_2010_71.
    1. Lener MS, et al. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biol Psychiatry. 2017;81:886–897. doi: 10.1016/j.biopsych.2016.05.005.
    1. Kao Chung-Feng, Chen Hui-Wen, Chen Hsi-Chung, Yang Jenn-Hwai, Huang Ming-Chyi, Chiu Yi-Hang, Lin Shih-Ku, Lee Ya-Chin, Liu Chih-Min, Chuang Li-Chung, Chen Chien-Hsiun, Wu Jer-Yuarn, Lu Ru-Band, Kuo Po-Hsiu. Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies. International Journal of Neuropsychopharmacology. 2016;19(12):pyw064. doi: 10.1093/ijnp/pyw064.
    1. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. The Psychiatric clinics of North America. 1999;22:667–673, ix-x. doi: 10.1016/S0193-953X(05)70101-5.
    1. Wang K, et al. Comparing the MicroRNA spectrum between serum and plasma. PLoS One. 2012;7:e41561. doi: 10.1371/journal.pone.0041561.
    1. Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7:e30679. doi: 10.1371/journal.pone.0030679.
    1. Gruzdev SK, Yakovlev AA, Druzhkova TA, Guekht AB, Gulyaeva NV. The Missing Link: How Exosomes and miRNAs can Help in Bridging Psychiatry and Molecular Biology in the Context of Depression, Bipolar Disorder and Schizophrenia. Cell Mol Neurobiol. 2019;39:729–750. doi: 10.1007/s10571-019-00684-6.
    1. Lee SY, et al. Serum DHEA-S concentration correlates with clinical symptoms and neurocognitive function in patients with bipolar II disorder: A case-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2017;74:31–35. doi: 10.1016/j.pnpbp.2016.11.006.
    1. Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci. 2012;125:7–17. doi: 10.1242/jcs.099200.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj