Abstract
We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.
Highlights
Genome wide association studies (GWAS), copy number variation (CNV) analysis and exome sequencing show that schizophrenia (SZ) and other neuropsychiatric disorders, including bipolar disorder (BD) and autism spectrum disorders (ASD), are genetically heterogeneous complex traits
Research on the potential role of miRNAs in 22q11.2 del-associated neuropsychiatric disorders has primarily focused on analyzing the effects of DGCR8 on miRNA expression and behavior, which stands to reason considering the effect it has on miRNA biogenesis [31,48,117]
There have been studies showing the effects of specific miRNAs that map to the deleted region, most notably MIR-185, which may influence neuronal function and synaptogenesis independently of DGCR8-mediated biogenesis [7,49,51,117]
Summary
Genome wide association studies (GWAS), copy number variation (CNV) analysis and exome sequencing show that schizophrenia (SZ) and other neuropsychiatric disorders, including bipolar disorder (BD) and autism spectrum disorders (ASD), are genetically heterogeneous complex traits This presents a potential problem in translating molecular and genetic findings into novel therapies that would benefit a large number of patients. Identifying downstream targets of SZ and ASD candidate genes that function as transcription factors, splicing factors or chromatin remodeling complexes is one potentially useful approach Another promising area of investigation in this regard is to characterize the role of microRNAs (miRNAs) in disease pathogenesis, considering their common mechanism of biogenesis and converging effect on genes involved in neurogenesis and synaptogenesis [1,2,3,4,5,6,7,8,9]. Most mRNAs are regulated by more than one miRNA, and any single miRNA can potentially interact with multiple mRNAs [14,15]
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