Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment

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.

Fig 1. GSA of SATB2_Cort in EA, and the partition of these SATB2 target genes into those that were or were not differentially expressed (DE) in P0 cortices of SATB2 WT v KO mice.

Gene-sets and number of genes are plotted on the y-axis. Beta values (effect sizes) as calculated by MAGMA are plotted on the x-axis with P-values shown above each data point. Horizontal bars indicate standard error. The overall enrichment signal (top) appears to be driven by those genes that were DE (bottom), indicating that of genes targeted and potentially regulated by SATB2, it is those functionally impacted by its loss that contribute more to EA.

Fig 2. GSA of SATB2_Hipp in EA in brain.

Gene-sets and number of genes are plotted on the y-axis. Beta values (effect sizes) as calculated by MAGMA are plotted on the x-axis with P-values shown above each data point. Horizontal bars indicate standard error. Analysis of non-brain and brain expressed genes, with the latter partitioned into SATB2+ or SATB2- based on genes being present in the SATB2_Hipp gene-set or not.

Fig 3. GSA of SATB2_Hipp in EA in hippocampus (Hipp).

Gene-sets and number of genes are plotted on the y-axis. Beta values (effect sizes) as calculated by MAGMA are plotted on the x-axis with P-values shown above each data point. Horizontal bars indicate standard error. Genes categorized as low, medium (med) or high expressed based on their expression in the human hippocampus at pcw 37–1 year and partitioned into SATB2+ and SATB- based on genes being present in the SATB2_Hipp gene-set or not.

Fig 4. GSA of SATB2_Hipp in EA in neurons.

Gene-sets and number of genes are plotted on the y-axis. Beta values (effect sizes) as calculated by MAGMA are plotted on the x-axis with P-values shown above each data point. Horizontal bars indicate standard error. Genes categorized as low, medium (med) or high expressed in neurons with medium and high sets partitioned into SATB2+ and SATB- based on genes being present in the SATB2_Hipp gene-set or not.

Fig 5. GSA of SATB2_Hipp in EA at the synapse.

Gene-sets and number of genes are plotted on the y-axis. Beta values (effect sizes) as calculated by MAGMA are plotted on the x-axis with P-values shown above each data point. Horizontal bars indicate standard error. High expressed genes in neurons were partitioned into those with potentially synaptic functions or not. Those with synaptic functions are further partitioned into SATB2+ or SATB2- based on genes being present in the SATB2_Hipp gene-set or not.