Schizophrenia is a severe mental disease characterized with positive symptoms, negative symptoms, and cognitive impairments. Although recent genome‐wide association studies (GWASs) have identified over 145 risk loci for schizophrenia, pinpointing the causal variants and genes at the reported loci and elucidating their roles in schizophrenia remain major challenges. Here we identify a functional single‐nucleotide polymorphism (SNP; rs213237) in ZNF323 promoter by using functional fine‐mapping. We found that allelic differences at rs213237 affected the ZNF323 promoter activity significantly. Consistently, expression quantitative trait loci (eQTL) analysis showed that rs213237 was significantly associated with ZNF323 expression in diverse human brain tissues, suggesting that rs213237 may contribute to schizophrenia risk through regulating ZNF323 expression. Interestingly, we found that ZNF323 protein was localized in the nucleus and knockdown of ZNF323 in macaque neural stem cells (mNSCs) significantly impaired proliferation and survival of mNSCs. We further showed that stable knockdown of ZNF323 in SH‐SY5Y cells resulted in significant decrease of the tyrosine hydroxylase (TH) protein expression. Finally, transcriptome analysis revealed that ZNF323 may regulate pivotal schizophrenia risk genes (including VIPR2 and NPY) and schizophrenia‐associated pathways (including PI3K‐AKT and NOTCH signaling pathways), suggesting that ZNF323 may be a major regulator of schizophrenia risk genes. Our study reveals how a genetic variant in ZNF323 promoter contributes to schizophrenia risk through regulating ZNF323 expression. More importantly, our findings demonstrate that ZNF323 may have a pivotal role in schizophrenia pathogenesis through regulating schizophrenia risk genes and schizophrenia‐associated biological processes (including neurodevelopment, PI3K‐AKT, and NOTCH signaling pathways).

中文翻译：

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功能变异精细定位和基因功能表征为 ZNF323 在精神分裂症发病机制中的作用提供了见解

精神分裂症是一种以阳性症状、阴性症状和认知障碍为特征的严重精神疾病。尽管最近的全基因组关联研究 (GWAS) 已经确定了超过 145 个精神分裂症的风险基因座，但在报告的基因座上精确定位因果变异和基因并阐明它们在精神分裂症中的作用仍然是主要挑战。在这里，我们通过使用功能精细定位确定了ZNF323启动子中的功能性单核苷酸多态性（SNP；rs213237）。我们发现 rs213237 的等位基因差异显着影响ZNF323启动子活性。一致地，表达数量性状基因座（eQTL）分析表明 rs213237 与ZNF323显着相关在不同的人脑组织中表达，表明 rs213237 可能通过调节ZNF323表达导致精神分裂症风险。有趣的是，我们发现 ZNF323 蛋白定位于细胞核中，在猕猴神经干细胞 (mNSCs) 中敲除 ZNF323 会显着损害 mNSCs 的增殖和存活。我们进一步表明，在 SH-SY5Y 细胞中稳定敲低ZNF323导致酪氨酸羟化酶 (TH) 蛋白表达显着降低。最后，转录组分析显示ZNF323可能调节关键的精神分裂症风险基因（包括VIPR2和NPY）和精神分裂症相关通路（包括 PI3K-AKT 和 NOTCH 信号通路），表明ZNF323可能是精神分裂症风险基因的主要调节因子。我们的研究揭示了ZNF323启动子中的遗传变异如何通过调节ZNF323表达来增加精神分裂症风险。更重要的是，我们的研究结果表明，ZNF323可能通过调节精神分裂症风险基因和精神分裂症相关生物过程（包括神经发育、PI3K-AKT 和 NOTCH 信号通路）在精神分裂症发病机制中发挥关键作用。