title: Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons.
abstract: OBJECTIVE
  Schizophrenia candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons. One important next step is to further our understanding on the role of activity-dependent changes of gene expression in the etiopathogenesis of schizophrenia.
  
  
  OBJECTIVE
  To examine whether neuronal activity-dependent changes of gene expression are dysregulated in schizophrenia.
  
  
  METHODS
  Neurons differentiated from human-induced pluripotent stem cells derived from 4 individuals with schizophrenia and 4 unaffected control individuals were depolarized using potassium chloride. RNA was extracted followed by genome-wide profiling of the transcriptome. Neurons were planted on June 21, 2013, and harvested on August 2, 2013.
  
  
  METHODS
  We performed differential expression analysis and gene coexpression analysis to identify activity-dependent or disease-specific changes of the transcriptome. Gene expression differences were assessed with linear models. Furthermore, we used gene set analyses to identify coexpressed modules that are enriched for schizophrenia risk genes.
  
  
  RESULTS
  We identified 1669 genes that were significantly different in schizophrenia-associated vs control human-induced pluripotent stem cell-derived neurons and 1199 genes that are altered in these cells in response to depolarization (linear models at false discovery rate ≤0.05). The effect of activity-dependent changes of gene expression in schizophrenia-associated neurons (59 significant genes at false discovery rate ≤0.05) was attenuated compared with control samples (594 significant genes at false discovery rate ≤0.05). Using gene coexpression analysis, we identified 2 modules (turquoise and brown) that were associated with diagnosis status and 2 modules (yellow and green) that were associated with depolarization at a false discovery rate of ≤0.05. For 3 of the 4 modules, we found enrichment with schizophrenia-associated variants: brown (χ2 = 20.68; P = .002), turquoise (χ2 = 12.95; P = .04), and yellow (χ2 = 15.34; P = .02).
  
  
  CONCLUSIONS
  In this analysis, candidate genes clustered within gene networks that were associated with a blunted effect of activity-dependent changes of gene expression in schizophrenia-associated neurons. Overall, these findings link schizophrenia candidate genes with specific molecular functions in neurons, which could be used to examine underlying mechanisms and therapeutic interventions related to schizophrenia.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York2Institute for Multiscale Biology, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York3Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, Bronx, New York.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: St Vincent's Clinical School and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales, Australia5Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Guennewig
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Dominik C
authors.initials: DC
authors.lastname: Kaczorowski
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Barry
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York7Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Brennand
mesh_terms: D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics