Biological underpinnings and genetic predisposition to schizophrenia within microrna-137 regulatory pathways across brain development

Previous studies have evaluated the role of the microRNA-137 (miRNA137) regulatory pathway in schizophrenia by using in silico or in vitro predicted target genes. These approaches do not capture the dynamic spatiotemporal nature of the miRNA137 regulatory pathway or tend to overestimate direct miRNA binding sites. To provide a more accurate representation of the miRNA137 pathway during human brain development, we evaluated the biological functionality of direct ex vivo miRNA137 targets previously documented in the early prenatal and adult brain. We studied the role of differential expression and genetic predisposing variation to schizophrenia and related disorders within these miRNA137 targets by gene set enrichment analyses (GSEA) and gene-set based polygenic score predictions in an independent schizophrenia case-control cohort. All results were compared to those from in silico or in vitro predicted targets. Only direct miRNA137 targets at prenatal and adult human brain displayed significant enrichments in synaptic and neuronal functions and captured the transcriptomic and genetic predisposing variation to schizophrenia. Furthermore, while adult target genes showed a more consistent enrichment in predisposing variation to schizophrenia and bipolar disorder in case/control polygenic models, prenatal target genes predicted negative symptomatology in schizophrenia patients. Our results suggest that using direct, temporally specific miRNA137 targets significantly improved the detection of biological mechanisms underlying its relationship with psychosis, clarified the association between schizophrenia and related conditions, and suggested association with specific symptomatology domains at different developmental stages of the disorder.