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

PLoS Genet. 2018 Jul 24;14(7):e1007515. doi: 10.1371/journal.pgen.1007515. eCollection 2018 Jul.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Academic Success
  • Animals
  • Axon Guidance / genetics
  • Cognition*
  • Corpus Callosum / growth & development
  • Corpus Callosum / metabolism
  • Datasets as Topic
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Developmental*
  • Genetic Predisposition to Disease
  • Genomics / methods
  • Hippocampus / growth & development
  • Hippocampus / metabolism
  • Humans
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / metabolism*
  • Mice
  • Mutation
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Schizophrenia / genetics*
  • Schizophrenia / pathology
  • Synaptic Transmission / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Matrix Attachment Region Binding Proteins
  • SATB2 protein, human
  • SATB2 protein, mouse
  • Transcription Factors

Grants and funding

This research was supported by Science Foundation Ireland (www.sfi.ie) grant 12/IP/1670 and Brain and Behavior Research Foundation NARSAD Independent Investigator Award (#25916). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.