Genome-Wide, Integrative Analysis Implicates Exosome-Derived MicroRNA Dysregulation in Schizophrenia

Abstract

Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.

Promoting Osteogenic Differentiation of Human Adipose-Derived Stem Cells by Altering the Expression of Exosomal miRNA

“…Dysregulation of exosome-derived miRNA expression has been reported in schizophrenia and localized breast cancer [53, 54]. These studies suggested that the expression of miRNAs in exosomes changed significantly under different conditions.…”

Epigenomic Dysregulation in Schizophrenia: In Search of Disease Etiology and Biomarkers

“…The observed up-regulation of miR-206 was accompanied by the down-regulation of its target, BDNF, in the blood. Since decreased expression of BDNF has been negatively associated with cognitive functions of animals, the researchers concluded that exosomal hsa-miR-206 up-regulation may contribute to BDNF dysfunction in schizophrenia, a finding which further supports the neurotrophin hypothesis of schizophrenia [94]. The details of miRNA studies covered in this section are summarized in Table 2.…”

Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability

“…miRNAs have also been profiled in the blood of patients with schizophrenia (89), with the main aim of identifying blood biomarkers of the disease. In a recent genome-wide expression study, Du et al (90) found that several miRNAs were differentially expressed in serum exosomes of patients with first-episode, drug-free schizophrenia relative to matched control subjects. Importantly, among the differentially expressed miRNAs, 11 could be used to dissociate schizophrenia samples from control samples with 75% to 90% accuracy (90).…”

“…In a recent genome-wide expression study, Du et al (90) found that several miRNAs were differentially expressed in serum exosomes of patients with first-episode, drug-free schizophrenia relative to matched control subjects. Importantly, among the differentially expressed miRNAs, 11 could be used to dissociate schizophrenia samples from control samples with 75% to 90% accuracy (90). Despite this remarkable precision, however, blood miRNA profiling tends to produce equivocal results in the context of schizophrenia, with biomarker candidates varying across independent studies (91)(92)(93).…”