title: Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia.
abstract: BACKGROUND
  Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls.
  
  
  METHODS
  We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that were non-conserved between adult cases and controls brain samples.
  
  
  RESULTS
  We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation.
  
  
  CONCLUSIONS
  This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. We showed that, although generated by different approaches, both sets of DEG associated to schizophrenia were involved with neocortical development. The results add to the hypothesis that critical metabolic changes may be occurring during early neurodevelopment influencing faulty development of the brain and potentially contributing to further vulnerability to the illness.
authors.affiliation: LIM23 (Medical Investigation Laboratory 23), University of Sao Paulo Medical School (USP), São Paulo, SP, Brazil. marianamasc@gmail.com.|Institute of Psychiatry-University of Sao Paulo, Medical School (FMUSP), São Paulo, SP, Brazil. marianamasc@gmail.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maschietto
authors.affiliation: LIM23 (Medical Investigation Laboratory 23), University of Sao Paulo Medical School (USP), São Paulo, SP, Brazil. tahira.ana@gmail.com.|Institute of Psychiatry-University of Sao Paulo, Medical School (FMUSP), São Paulo, SP, Brazil. tahira.ana@gmail.com.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Tahira
authors.affiliation: Hospital Israelita Albert Einstein, São Paulo, Brazil. renatopuga@gmail.com.
authors.forename: Renato
authors.initials: R
authors.lastname: Puga
authors.affiliation: Post-graduation Program Institute of Mathematics and Statistics, University of Sao Paulo, São Paulo, SP, Brazil. lelimaufc@gmail.com.
authors.forename: Leandro
authors.initials: L
authors.lastname: Lima
authors.affiliation: Post-graduation Program Institute of Mathematics and Statistics, University of Sao Paulo, São Paulo, SP, Brazil. danielbmariani@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mariani
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. bruna.paulsen@lance-ufrj.org.
authors.forename: Bruna da Silveira
authors.initials: Bda S
authors.lastname: Paulsen
authors.affiliation: Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 00006525@ufrgs.br.
authors.forename: Paulo
authors.initials: P
authors.lastname: Belmonte-de-Abreu
authors.affiliation: Post-graduation Program Institute of Mathematics and Statistics, University of Sao Paulo, São Paulo, SP, Brazil. enrikevieira@gmail.com.
authors.forename: Henrique
authors.initials: H
authors.lastname: Vieira
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil. ana.krepischi@gmail.com.
authors.forename: Ana Cv
authors.initials: AC
authors.lastname: Krepischi
authors.affiliation: International Research Center-AC Camargo Cancer Center, São Paulo, Brazil. dirce.carraro@cipe.accamargo.org.br.
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. japalha@ecsaude.uminho.pt.|ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal. japalha@ecsaude.uminho.pt.
authors.forename: Joana A
authors.initials: JA
authors.lastname: Palha
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. srehen@gmail.com.|D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil. srehen@gmail.com.
authors.forename: Stevens
authors.initials: S
authors.lastname: Rehen
authors.affiliation: LIM23 (Medical Investigation Laboratory 23), University of Sao Paulo Medical School (USP), São Paulo, SP, Brazil. helena.brentani@gmail.com.|Institute of Psychiatry-University of Sao Paulo, Medical School (FMUSP), São Paulo, SP, Brazil. helena.brentani@gmail.com.|Department of Psychiatry, University of Sao Paulo, Medical School (FMUSP), Rua Dr Ovídio Pires de Campos,785-CEP 05403-010, São Paulo, SP, Caixa Postal n 3671, Brazil. helena.brentani@gmail.com.|National Institute of Developmental Psychiatry for Children and Adolescents, CNPq, São Paulo, SP, Brazil. helena.brentani@gmail.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
mesh_terms: D001706:Biopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005625:Frontal Lobe / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction