Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons

Myocyte enhancer factor 2 C (MEF2C) is an important transcription factor during neurodevelopment. Mutation or deletion of MEF2C causes intellectual disability (ID) and common variants within MEF2C are associated with cognitive function and schizophrenia risk. We investigated if genes influenced by MEF2C during neurodevelopment are enriched for genes associated with neurodevelopmental phenotypes, and if this can be leveraged to identify biological mechanisms and individual brain cell types affected. We used a set of 1,052 genes that were differentially expressed in the adult mouse brain following early embryonic deletion of Mef2c in excitatory cortical neurons. Using GWAS data, we found these differentially expressed genes (DEGs) to be enriched for genes associated with schizophrenia, intelligence and educational attainment but not autism spectrum disorder (ASD). Using sequencing data from trios studies, we found these DEGs to be enriched for genes containing de novo mutations reported in ASD and ID, but not schizophrenia. Using single cell RNA-seq data, we identified that a number of different excitatory glutamatergic neurons in the cortex were enriched for these DEGs including deep layer pyramidal cells and cells in the retrosplenial cortex, entorhinal cortex and subiculum. These data indicate that genes influenced by MEF2C during neurodevelopment contribute to cognitive function and risk of neurodevelopmental disorders. Within excitatory neurons, common SNPs in these genes contribute to cognition and SZ risk via an effect on synaptic function based on gene ontology analysis. In contrast, rare mutations contribute to earlier onset ASD and ID via an effect on cell morphogenesis.Author SummarySchizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability. Here we take an individual gene identified in genetic studies of schizophrenia and cognition called MEF2C, which on its own is a very important regulator of brain development. We use data from a mouse study where MEF2C has been stopped from functioning or knocked out during brain development. The effect of that knock out has been measured when the mice reach adulthood, in the form of a set of differentially expressed genes (DEGs) from the somatosensory cortex. We found that this set of DEGs contains more genes than expected by chance that are associated with schizophrenia and cognition or contain rare new (de novo) mutations reported in autism and intellectual disability. Using gene expression data from single brain cells, we identified that a number of specific excitatory glutamatergic neurons in the cortex were enriched for these DEGs. This study provides evidence that the molecular mechanisms that underpin schizophrenia and cognitive function include disruption of cell types influenced by MEF2C.