Abstract
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 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.
Highlights
Neocortical organization and circuitry requires the coordinated execution of a series of developmental processes, including the specification of neuronal identity, neuronal migration, and wiring of neural circuits [1]
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
We show that these gene sets are enriched for common variants associated with schizophrenia and educational attainment, and for rare variants that increase risk of various neurodevelopmental disorders
Summary
Neocortical organization and circuitry requires the coordinated execution of a series of developmental processes, including the specification of neuronal identity, neuronal migration, and wiring of neural circuits [1]. SATB2 modifies higher-order chromatin structure and can mediate chromatin loop formation via self-association in order to regulate other genes [3,4,5,6]. Pyramidal neurons (excitatory projection neurons primarily found in the cerebral cortex [8]) project axons across multiple brain regions and to the corticospinal tract [9]. Based on their projections, pyramidal neurons can be divided into two groups; deep layer neurons (located in cortical layers 5 and 6) projecting to subcortical regions and upper layer neurons (located in cortical layers 2, 3 and 4) projecting across the corpus callosum to the contralateral hemisphere[10]. In the adult CNS, SATB2 is critically important as a regulator of synaptic plasticity in the hippocampus that underlies memory functions [13,14]
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