β-Catenin promoter chip-chip reveals potential schizophrenia and bipolar disorder gene network

Erika Pedrosa, Abhishek Shah, Christopher Tenore, Michael Capogna, Catalina Villa, Xingyi Guo, Deyou Zheng, Herbert M. Lachman

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Therapeutic concentrations of lithium salts inhibit glycogen synthase kinase 3 beta (GSK3β) and phosphoinositide (PI) signaling suggesting that abnormal activation of these pathways could be a factor in the pathophysiology of bipolar disorder (BD). Involvement of these pathways is also supported by recent genome-wide association studies (GWASs). One way investigators have investigated the molecular basis of BD and the therapeutic action of lithium is by microarray expression studies, since both GSK3β-and PI-mediated signal transduction pathways are coupled to transcriptional activation and inhibition. However, expression profiling has some limitations and investigators cannot use the approach to analyze fetal brain tissue, arguably the most relevant biological structure related to the development of genetically based psychiatric disorders. To address these shortcomings, the authors have taken a novel approach using chromatin immunoprecipitation-enriched material annealed to microarrays (ChIP-chip) targeting genes in fetal brain tissue bound by β-catenin, a transcription factor that is directly regulated by GSK3β. The promoters for 640 genes were found to be bound by β-catenin, many of which are known schizophrenia (SZ), autism spectrum disorder (ASD), and BD candidates, including CACNA1B, NRNG, SNAP29, FGFR1, PCDH9, and nine others identified in recently published GWASs and genome-wide searches for copy number variants (CNVs). The findings suggest that seemingly disparate candidate genes for SZ and BD can be incorporated into a common molecular network revolving around GSK3β/β-catenin signaling. In addition, the finding that a putative lithium-responsive pathway may influence a subgroup of SZ and ASD candidate genes could have therapeutic implications.

Original languageEnglish (US)
Pages (from-to)182-193
Number of pages12
JournalJournal of Neurogenetics
Volume24
Issue number4
DOIs
StatePublished - Dec 2010

Keywords

  • Chip
  • GSK3β
  • bipolar disorder
  • chromatin
  • lithium schizophrenia

ASJC Scopus subject areas

  • Genetics
  • Cellular and Molecular Neuroscience

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