The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice
Background Chromosome 16p11.2 is one of the most significant loci in the genome-wide association study (GWAS) of schizophrenia.  Despite several integrative analyses and functional genomics studies have been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. Methods We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus.  We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of Adeno-associated Virus (AAV), followed by behavioral assessments, dendritic spine analyses and RNA sequencing. Findings We identified significant associations between elevated INO80E mRNA expression in frontal cortex and risk of schizophrenia.  The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviors, including increased anxiety behavior, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group.  The neuronal sparse labeling assay showed that the density of mushroom spines in the pyramidal neurons of mPFC was significantly decreased in Ino80e-OE mice compared with control mice, accompanied by a notable increase in the density of stubby spines.  Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e . Interpretation Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviors in mice, further supporting the hypothesis that INO80E is an authentic risk gene. Overall design: We first identified schizophrenia risk genes at the 16p11.2 GWAS locus by expression quantitative trait loci (eQTL) and Mendelian randomization (SMR) analysis based on aggregated data. Then we constructed the Adeno-associated Virus(AAV). We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using  stereotaxic injection of Adeno-associated Virus (AAV). We then performed behavioral assessment, dendritic spine analysis, and RNA sequencing to assess the difference between the murine model with dysregulated expression of risk gene and that of the control murine.