Preliminary Clinical Verification Of MicroRNA As Specific Schizophrenia Biomarker

Schizophrenia (SZ) is one of the most severely debilitating and complex neuropsychiatricdisorders afflicting an estimated1%of the adult population worldwide throughout life. It ischaracterized by various groups of clinical symptoms and wide-ranging deficits inneurocognitive and neurophysiological functions, imposing enormous burden on individual,family and society. In spite of the fact that developments in neural imaging, proteomics,immunohistochemistry and histological techniques keep refining our understanding of thespectrum of changes in neural circuitry, synaptic plasticity and cytoarchitecture, thepathophysiology of SZ remains elusive. However, general agreement on etiology of SZ hasbeen reached that both environmental and genetic factors contribute to its development.The evidences supporting the view that schizophrenia is in large r part a genetically baseddisorder are overwhelming. As early intervention in schizophrenia is thought to beimportant in improving outcome, any delay in diagnosis or misdiagnosis owing to theinherent limitations of clinical descriptors may have a negative prognostic impact.Consequently, accessible biological markers are needed to improve the timing andaccuracy of diagnosis, and identify individuals at very high risk of schizophrenia.MicroRNAs (miRNAs) are a large family of single-stranded small non-coding RNAsof19-23nucleotides in length, regulating almost all biological processes through silencingthe gene expression at the post-transcriptional level. The evidence that miRNAs regulatemany aspects of the neural structure and function at multiple levels strongly suggests thatthe alterations in miRNA expression might contribute to the genetic and biological basis ofneuropsychiatric disorders. Furthermore, a link between structurally or quantitativelyaltered miRNAs and risk of neuropsychiatric disorders has been established. In the earlystage of schizophrenia research, expression profiling studies in postmortem gray matter ofindividuals with schizophrenia, involving various brain regions including the prefrontalcortex (BA9, BA10,BA46), parietal (BA7) and temporal cortices (BA22), have implicatednumerous miRNAs associated with this disorder. It has to be considered that studiesconducted in post mortem specimens are greatly crippled by unavailability of brain tissue.On the other hand, as exemplified by the parallel changes in the levels of certain mRNAsbetween the CNS and peripheral blood, it is plausible to suggest that disease associatedchanges in miRNA expression might also be detectable in peripheral tissues such as plasmaand lymphocytes. Since brain tissue is not readily accessible, blood-based expression profiling is increasingly being undertaken to search for potential biomarkers forschizophrenia. The circulating miRNAs are sufficiently stable and detectable to serve asclinical biomarkers.In this study, we selected9SZ-associated miRNAs (miR-30e, miR-34a, miR-181b,miR-195, miR-346, miR-432, miR-7, miR-132and miR-212) based upon adequateliterature survey for clinical differential investigation by quantitative PCR betweenschizophrenia and healthy controls in61versus62paired sample, in an effort to explorepotential specific diagnostic SZ biomarker. We then randomly selected25out of theschizophrenia group for the following six-week long medication controlled course(olanzapine, quetiapine, risperidone and ziprasidone) to investigate antipsychotic effectsupon miRNA expression by applying quantitative PCR(qPCR) after three and six weeks oftreatment, in an effort to validate clinically miRNA as specific schizophrenia biomarker.An array of scales, including Positive And Negative Syndrome Scale (PANSS) and GlobalAssessment Scale (GAS), were also administered to the selected25schizophrenia patientsafter three and six weeks of treatment. The results revealed that the expression levels ofmiR-30e, miR-34a, miR-181b, miR-346and miR-7in SZ group were significantlyup-regulated compared with the control group (p<0.05～p<0.001). ROC curves analysisrevealed that these five miRNA as a combined biomarker had significantly diagnosticvalue in differentiating SZ (AUC was0.713, sensitivity and specificity were35.5%and90.2%respectively); Logistic regression analysis demo nstrated that miR-181b had thegreatest relative risk against SZ (Odd Ratio was2.483); Peripheral miR-30e, miR-181b,miR-132and miR-432expression were significantly down-regulated after medication(p<0.05~p<0.01); the changes of miR-30e, miR-132, miR-212and miR-181b expressionlevel significantly correlated with the changes of PANSS total score and GAS score alongthe treatment course (p<0.05).We conclude that miR-30e, miR-34a, miR-181b, miR-346and miR-7might serve asspecific combined SZ biomarkers for SZ diagnosis, and peripheral miR-30e, miR-181b andmiR-132combined as a panel might serve as potential specific biomarkers for SZprognosis.