Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

Matthew J. Hill, Marc P. Forrest, Enca Martin-Rendon, Derek J. Blake*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Genome wide association studies (GWAS) have revolutionized the study of complex diseases and have uncovered common genetic variants associated with an increased risk for major psychiatric disorders. A recently published schizophrenia GWAS replicated earlier findings implicating common variants in Transcription factor 4 (TCF4) as susceptibility loci for schizophrenia. By contrast, loss of function TCF4 mutations, although rare, cause Pitt-Hopkins syndrome (PTHS); a disorder characterized by intellectual disability (ID), developmental delay and behavioral abnormalities. TCF4 mutations have also been described in individuals with ID and non-syndromic neurodevelopmental disorders. TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that regulate gene expression at E-box-containing promoters and enhancers. Accordingly, TCF4 has an important role during brain development and can interact with a wide array of transcriptional regulators including some proneural factors. TCF4 may, therefore, participate in the transcriptional networks that regulate the maintenance and differentiation of distinct cell types during brain development. Here, we review the role of TCF4 variants in the context of several distinct brain disorders associated with impaired cognition.

Original languageEnglish (US)
Pages (from-to)206-214
Number of pages9
JournalCurrent Behavioral Neuroscience Reports
Issue number4
StatePublished - Dec 1 2014
Externally publishedYes


  • Intellectual disability
  • Neurodevelopment
  • Pitt-Hopkins syndrome
  • Schizophrenia
  • Transcription

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Behavioral Neuroscience


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