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.

中文翻译：

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患者来源的神经祖细胞中的基因表达表明 WNT5A 信号通路与精神分裂症的病因有关

背景技术精神分裂症的全基因组关联研究表明，非编码区的变异是造成该疾病的大部分常见变异遗传性的原因。据推测，这些风险变异会改变基因表达。因此，研究精神分裂症基因表达的改变可能为了解该病的病因学提供一种直接的方法。在这项研究中，我们使用来自嗅神经上皮细胞（CNON 细胞）的培养神经祖细胞作为遗传未改变的细胞模型来阐明精神分裂症的神经发育方面。方法 我们使用来自 111 名对照受试者和 144 名精神分裂症患者的 CNON 细胞的 RNA 测序进行了基因表达研究。差异表达基因用DESeq2软件鉴定，使用协变量校正性别、年龄、文库批次和 1 个替代变量成分。结果 共有 80 个基因差异表达（错误发现率 < 10%），在细胞迁移、细胞粘附、发育过程、突触组装、细胞增殖和相关基因本体类别中表现出富集。钙粘蛋白和 Wnt 信号通路在过度表达测试中呈阳性，此外，许多基因特异性参与 WNT5A 信号传导。差异表达的基因适度但显着地富集在与精神分裂症的精神病基因组学联盟全基因组关联研究的全基因组显着关联的重叠单核苷酸多态性的基因中。我们还发现与其他精神疾病或大脑发育相关的基因存在大量重叠，在与精神分裂症中具有从头突变的基因相同的基因本体论类别中富集，以及对诱导多能干细胞衍生的神经祖细胞的研究。结论 CNON 细胞是精神分裂症神经发育方面的良好模型，可用于阐明该疾病的病因。