Background: Chromosome 16p11.2 is one of the most significant loci in the genome-wide association studies (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies having 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 a murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of adeno-associated virus (AAV), followed by behavioural assessments, dendritic spine analyses and RNA sequencing.

Findings: We identified significant associations between elevated INO80E mRNA expression in the frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviours, including increased anxiety behaviour, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labelling assay showed that the density of stubby spines in the pyramidal neurons of mPFC was significantly increased in Ino80e-OE mice compared with control mice. 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 behaviours in mice, further supporting the hypothesis that INO80E is an authentic risk gene.

Funding: This project received support from the National Key Research and Development Program of China, National Natural Science Foundation of China, Key Research and Development Projects of Hunan Provincial Science and Technology Department, Science and Technology Innovation team of Hunan Province, etc.