Gene Expression in Patient-Derived Neural Progenitors Implicates WNT5A Signaling in the Etiology of Schizophrenia

Oleg V. Evgrafov, Chris Armoskus, Bozena B. Wrobel, Valeria N. Spitsyna, Tade Souaiaia, Jennifer S. Herstein, Christopher P. Walker, Joseph D. Nguyen, Adrian Camarena, Jonathan R. Weitz, Jae Mun “Hugo” Kim, Edder Lopez Duarte, Kai Wang, George M. Simpson, Janet L. Sobell, Helena Medeiros, Michele T. Pato, Carlos N. Pato, James A. Knowles

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background: Genome-wide association studies of schizophrenia have demonstrated that variations in noncoding regions are responsible for most of the common variation heritability of the disease. It is hypothesized that these risk variants alter gene expression. Therefore, studying alterations in gene expression in schizophrenia may provide a direct approach to understanding the etiology of the disease. In this study we use cultured neural progenitor cells derived from olfactory neuroepithelium (CNON cells) as a genetically unaltered cellular model to elucidate the neurodevelopmental aspects of schizophrenia. Methods: We performed a gene expression study using RNA sequencing of CNON cells from 111 control subjects and 144 individuals with schizophrenia. Differentially expressed genes were identified with DESeq2 software, using covariates to correct for sex, age, library batches, and 1 surrogate variable component. Results: A total of 80 genes were differentially expressed (false discovery rate < 10%), showing enrichment in cell migration, cell adhesion, developmental process, synapse assembly, cell proliferation, and related Gene Ontology categories. Cadherin and Wnt signaling pathways were positive in overrepresentation test, and, in addition, many genes were specifically involved in WNT5A signaling. The differentially expressed genes were modestly, but significantly, enriched in the genes overlapping single nucleotide polymorphisms with genome-wide significant association from the Psychiatric Genomics Consortium genome-wide association study of schizophrenia. We also found substantial overlap with genes associated with other psychiatric disorders or brain development, enrichment in the same Gene Ontology categories as genes with mutations de novo in schizophrenia, and studies of induced pluripotent stem cell–derived neural progenitor cells. Conclusions: CNON cells are a good model of the neurodevelopmental aspects of schizophrenia and can be used to elucidate the etiology of the disorder.

Original languageEnglish (US)
Pages (from-to)236-247
Number of pages12
JournalBiological Psychiatry
Volume88
Issue number3
DOIs
StatePublished - Aug 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Keywords

  • Cell culture
  • Neural progenitors
  • Olfactory neuroepithelium
  • RNA-seq
  • Schizophrenia
  • WNT5A signaling

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