Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment
SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used
... gnition. We used data from Satb2 mouse models to generate three gene-sets that contain genes either functionally related to SATB2 or targeted by SATB2 at different stages of development. Each was tested for enrichment using the largest available genome-wide association studies (GWAS) datasets for schizophrenia and educational attainment (EA) and enrichment analysis was also performed for schizophrenia and other neurodevelopmental disorders using data from rare variant sequencing studies. These SATB2 gene-sets were enriched for genes containing common variants associated with schizophrenia and EA, and were enriched for genes containing rare variants reported in studies of schizophrenia, autism and intellectual disability. In the developing cortex, genes targeted by SATB2 based on ChIP-seq data, and functionally affected when SATB2 is not expressed based on differential expression analysis using RNA-seq data, show strong enrichment for genes associated with EA. For genes expressed in the hippocampus or at the synapse, those targeted by SATB2 are more strongly enriched for genes associated EA than gene-sets not targeted by SATB2. This study demonstrates that single gene findings from GWAS can provide important insights to pathobiological processes. In this case we find evidence that genes influenced by SATB2 and involved in synaptic transmission, axon guidance and formation of the corpus callosum are contributing to schizophrenia and cognition. Schizophrenia is a complex disorder caused by many genes. Using new gene discoveries to understand pathobiology is a foundation for development of new treatments. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability, leading to unemployment, homelessness and social isolation. Genome-wide association studies (GWAS) of schizophrenia have been effective at identifying individual SNPs and genes that contribute to risk but have struggled to immediately uncover the bigger picture of the underlying biology of the disorder. Here we take an individual gene identified in a schizophrenia GWAS called SATB2, which on its own is a very important regulator of brain development. We use functional genomics data from mouse studies to identify sets of others genes that are influenced by SATB2 during development. We show that these gene sets are enriched for common variants associated with schizophrenia and educational attainment (used as a proxy for cognition), and for rare variants that increase risk of various neurodevelopmental disorders. This study provides evidence that the molecular mechanisms that underpin schizophrenia and cognitive function include disruption of biological processes influenced by SATB2 as the brain is being organized and wired during development. SATB2 in schizophrenia and cognition PLOS Genetics | https://doi.