Schizophrenia (SZ) is a disease that causes mental disability and affects 1% of the total population in the world. Our aim was to identify new molecular targets that would help to diagnose and treat these patients. The GSE54578 microRNA expression profile was downloaded from the Gene Expression Omnibus database that consists of peripheral blood samples of 15 first-onset SZ patients and 15 healthy controls. Principal-component analysis-based unsupervised feature extraction (FE), protein–protein interaction network, and pathway enrichment were performed, and microRNA (miRNA)-hub gene network was established. A set of seven miRNA (hsa-miR-373-5p, hsa-miR-199a-3p, hsa-miR-22-5p, hsa-miR-4711-3p, hsa-miR-3157-3p, hsa-miR-542-5p, and hsa-miR-3615) could successfully discriminate SZ patients from healthy controls with high accuracy. We identified two miRNAs (hsa-miR-373-5p and hsa-miR-199a-3p) as a signature that mostly related to SZ. These miRNAs could be potential novel biomarkers and could contribute to the clinical treatment of this disease.
Get full access to this article
View all access options for this article.
References
1.
BarakY., AchironA., MandelM., et al.2005. Reduced cancer incidence among patients with schizophrenia. Cancer. 104, 2817–2821.
2.
BenjaminiY., and HochbergY.1995. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J. R. Stat. Soc. Series B Methodol. 57, 289–300.
3.
BeveridgeN.J., and CairnsM.J.2012. MicroRNA dysregulation in schizophrenia. Neurobiol. Dis. 46, 263–271.
4.
BeveridgeN.J., GardinerE., CarrollA.P., et al.2010. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol. Psychiatry. 15, 1176–1189.
5.
BravoJ.A., and DinanT.G.2011. MicroRNAs: A novel therapeutic target for schizophrenia. Curr. Pharm. Des. 17, 176–188.
6.
BrenningA., and LausenB.2008. Estimating error rates in the classification of paired organs. Stat. Med. 27, 4515–4531.
7.
BrunetA., DattaS.R., and GreenbergM.E.2001. Transcription-dependent and-independent control of neuronal survival by the PI3K–Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297–305.
8.
CaputoV., CiolfiA., MacriS., et al.2015. The emerging role of MicroRNA in schizophrenia. CNS Neurol. Disord. Drug Targets. 14, 208–221.
9.
CarboniL., MarchettiL., LauriaM., et al.2018. Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression. Neuropsychopharmacology. 43, 2134.
10.
ChangX., LimaL.A., LiuY., et al.2018. Common and Rare Genetic Risk Factors Converge in Protein Interaction Networks Underlying Schizophrenia. Front. Genet. 9, 434.
11.
ChouF.H., TsaiK.Y., SuC.Y., et al.2011. The incidence and relative risk factors for developing cancer among patients with schizophrenia: A nine-year follow-up study. Schizophr. Res. 129, 97–103.
12.
FawcettT.2006. An introduction to ROC analysis. Pattern Recogn. Lett. 27, 861–874.
13.
GardinerE., BeveridgeN.J., WuJ.Q., et al.2012. Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol. Psychiatry. 17, 827–840.
14.
HaubergM.E., RoussosP., GroveJ., et al.2016. Analyzing the Role of MicroRNAs in Schizophrenia in the context of common genetic risk variants. JAMA Psychiatry. 73, 369–377.
15.
HaunsbergerS.J., ConnollyN.M., and PrehnJ.H.2016. miRNAmeConverter: An R/bioconductor package for translating mature miRNA names to different miRBase versions. Bioinformatics. 33, 592–593.
16.
HeK., GuoC., HeL., et al.2018. MiRNAs of peripheral blood as the biomarker of schizophrenia. Hereditas. 155, 9.
17.
Hippisley-CoxJ., VinogradovaY., CouplandC., et al.2007. Risk of malignancy in patients with schizophrenia or bipolar disorder: Nested case-control study. Arch. Gen. Psychiatry. 64, 1368–1376.
18.
Huang daW., ShermanB.T., and LempickiR.A.2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57.
19.
JanoutovaJ., JanackovaP., SeryO., et al.2016. Epidemiology and risk factors of schizophrenia. Neuro. Endocrinol. Lett. 37, 1–8.
20.
JeffriesC.D., PerkinsD.O., ChandlerS.D., et al.2016. Insights into psychosis risk from leukocyte microRNA expression. Transl. Psychiat. 6, e981.
21.
KaneJ.M., and CorrellC.U.2010. Pharmacologic treatment of schizophrenia. Dialogues Clin. Neurosci. 12, 345.
22.
LaiC.Y., YuS.L., HsiehM.H., et al.2011. MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. Plos One. 6, e21635.
23.
LeS., JosseJ., and HussonF.2008. FactoMineR: An R package for multivariate analysis. J. Stat. Softw. 25, 1–18.
24.
LichtermannD., EkelundJ., PukkalaE., et al.2001. Incidence of cancer among persons with schizophrenia and their relatives. Arch. Gen. Psychiatry. 58, 573–578.
25.
MaL., and WeinbergR.A.2008. MicroRNAs in malignant progression. Cell cycle. 7, 570–572.
26.
ManchiaM., PirasI.S., HuentelmanM.J., et al.2017. Pattern of gene expression in different stages of schizophrenia: Down-regulation of NPTX2 gene revealed by a meta-analysis of microarray datasets. Eur. Neuropsychopharmacol. 27, 1054–1063.
27.
MayilyanK.R., WeinbergerD.R., and SimR.B.2008. The complement system in schizophrenia. Drug News Perspect. 21, 200.
28.
PolterA., YangS., ZmijewskaA.A., et al.2009. Forkhead box, class O transcription factors in brain: Regulation and behavioral manifestation. Biol. Psychiatry. 65, 150–159.
29.
RuY., KechrisK.J., TabakoffB., et al.2014. The multiMiR R package and database: Integration of microRNA–target interactions along with their disease and drug associations. Nucleic Acids Res. 42, e133.
30.
ShannonP., MarkielA., OzierO., et al.2003. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504.
31.
SheinermanK.S., and UmanskyS.R.2013. Circulating cell-free microRNA as biomarkers for screening, diagnosis and monitoring of neurodegenerative diseases and other neurologic pathologies. Front. Cell Neurosci. 7, 150.
32.
SzklarczykD., GableA.L., LyonD., et al.2018. STRING v11: Protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607–D613.
33.
TaguchiY.2016. Identification of more feasible microRNA–mRNA interactions within multiple cancers using principal component analysis based unsupervised feature extraction. Int. J. Mol. Sci. 17, 696.
34.
TaguchiY.H.2017. Identification of candidate drugs using tensor-decomposition-based unsupervised feature extraction in integrated analysis of gene expression between diseases and DrugMatrix datasets. Sci Rep-Uk. 7, 13733.
35.
TaguchiY.H., and WangH.2017. Genetic Association between Amyotrophic Lateral Sclerosis and Cancer. Genes-Basel. 8, 243.
36.
TeamT.R.D.C. 2010. R: A Language and Environment for Statistical Computing (www.R.project.org).
37.
WakefieldJ.C.2010. Misdiagnosing normality: Psychiatry's failure to address the problem of false positive diagnoses of mental disorder in a changing professional environment. J. Public Ment. Health. 19, 337–351.
38.
WangH., QuirionR., LittleP.J., et al.2015. Forkhead box O transcription factors as possible mediators in the development of major depression. Neuropharmacology. 99, 527–537.
39.
WangY., XueD., LiY., et al.2016. The Long Noncoding RNA MALAT-1 is A Novel Biomarker in Various Cancers: A Meta-analysis Based on the GEO Database and Literature. J. Cancer. 7, 991–1001.
40.
WenQ., WangH., LittleP.J., et al.2012. Forkhead family transcription factor FoxO and neural differentiation. Neurogenetics. 13, 105–113.
41.
WuJ.Q., GreenM.J., GardinerE.J., et al.2016. Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis. Brain Behav. Immun. 53, 194–206.
42.
XuB., HsuP.-K., StarkK.L., et al.2013. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell. 152, 262–275.
43.
YuH.C., WuJ., ZhangH.X., et al.2015. Alterations of miR-132 are novel diagnostic biomarkers in peripheral blood of schizophrenia patients. Prog. Neuropsychopharmacol. Biol. Psychiatry. 63, 23–29.
44.
ZhangF., XuY., ShugartY.Y., et al.2015. Converging evidence implicates the abnormal microRNA system in schizophrenia. Schizophr. Bull. 41, 728–735.
45.
ZhengH., LiuJ.-Y., SongF.-J., et al.2013. Advances in circulating microRNAs as diagnostic and prognostic markers for ovarian cancer. Cancer Biol. Med. 10, 123.
