Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the AS3MT gene. Although AS3MT is hypothesized to play a role in neuronal development and differentiation, work to fully understand the function of this gene has been limited. In this study we explored the function of AS3MT using a neuronal cell line (SH-SY5Y). We confirm previous findings of isoform specific expression of AS3MT during SH-SY5Y differentiation toward neuronal fates. Using CRISPR-Cas9 gene editing we generated AS3MT knockout SH-SY5Y cell lines and used RNA-seq to identify significant changes in gene expression in pathways associated with neuronal development, inflammation, extracellular matrix formation, and RNA processing, including dysregulation of other genes strongly implicated in schizophrenia. We did not observe any morphological changes in cell size and neurite length following neuronal differentiation and MAP2 immunocytochemistry. These results provide novel insights into the potential role of AS3MT in brain development and identify pathways through which genetic variation in this region may confer risk for schizophrenia.

中文翻译：

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精神分裂症相关基因 AS3MT 的功能表征确定了在神经元发育中的作用

全基因组关联研究 (GWAS) 已经确定了与精神分裂症相关的多个基因组区域，尽管许多变体位于以高度连锁不平衡 (LD) 为特征的非编码区域，这使得阐明分子机制具有挑战性。染色体 10q24 上的基因组区域一直与精神分裂症相关，其风险归因于AS3MT基因。尽管假设AS3MT在神经元发育和分化中发挥作用，但充分了解该基因功能的工作受到限制。在这项研究中，我们使用神经元细胞系 (SH-SY5Y)探索了AS3MT的功能。我们证实了先前对AS3MT亚型特异性表达的发现在 SH-SY5Y 向神经元命运分化的过程中。使用 CRISPR-Cas9 基因编辑，我们生成了 AS3MT敲除 SH-SY5Y 细胞系，并使用 RNA-seq 来识别与神经元发育、炎症、细胞外基质形成和 RNA 加工相关的通路中基因表达的显着变化，包括其他基因的强烈失调与精神分裂症有关。我们没有观察到神经元分化和 MAP2 免疫细胞化学后细胞大小和神经突长度的任何形态变化。这些结果为AS3MT在大脑发育中的潜在作用提供了新的见解，并确定了该区域的遗传变异可能导致精神分裂症风险的途径。