Abstract
Since brain tissue is not readily accessible, a new focus in search of biomarkers for schizophrenia is blood-based expression profiling of non-protein coding genes such as microRNAs (miRNAs), which regulate gene expression by inhibiting the translation of messenger RNAs. This study aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set of 60 cases and 30 controls. The expression levels of the miRNA signature were then evaluated for their correlation with the patients' clinical symptoms, neurocognitive performances, and neurophysiological functions. A seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in the testing set, with an AUC of 85%. Among these miRNAs, miR-34a was differentially expressed between cases and controls in both the learning (P = 0.005) and the testing set (P = 0.002). These miRNAs were differentially correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation.
Highlights
Schizophrenia is a common and often disabling mental illness characterized by a varied group of clinical symptoms [1] and wide-ranging deficits in neurocognitive and neurophysiological functions [2,3,4]
Out of the 365 miRNAs assayed using the Taqman Low Density Array (TLDA) in the learning set of 30 schizophrenia patients and 30 controls, the expression levels of 221 (60.5%) were detectable in the peripheral mononuclear leukocytes of $30% of the samples in either the schizophrenia patients or the controls
Our two-staged search for miRNAs with aberrant levels in blood mononuclear leukocytes revealed a combination of seven miRNA expression alterations to have robustly high discriminating accuracy for schizophrenia
Summary
Schizophrenia is a common and often disabling mental illness characterized by a varied group of clinical symptoms [1] and wide-ranging deficits in neurocognitive and neurophysiological functions [2,3,4]. The underlying pathophysiology of schizophrenia remains not well understood, dysregulations of its susceptibility genes are likely to converge functionally upon illness risk [5], which may manifest as certain endophenotypes, such as abnormalities in sustained attention, executive function, or eventrelated potentials [6,7]. Biomarkers that reflect these dysregulations for schizophrenia have the potential to substantially improve the clinical management of the disorder and even revolutionize its drug development approaches [8,9]. The peripheral expression levels of some dysregulated genes were found to be correlated with certain clinical symptoms and neurocognitive functions in patients with schizophrenia [18]
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