Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene

	Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene
	Zhang, Y; Li, SW; Li, XY; Yang, YF; Li, WQ; Xiao, X; Li, M; Lv, LX; Luo, XJ
	2021
发表期刊	JOURNAL OF MEDICAL GENETICS
ISSN	0022-2593
卷号	58 期号:10 页码:666-678
摘要	The association between NOTCH4 and schizophrenia has been repeatedly reported. However, the results from different genetic studies are inconsistent, and the role of NOTCH4 in schizophrenia pathogenesis remains unknown. Here, we provide convergent lines of evidence that support NOTCH4 as a schizophrenia risk gene. We first performed a meta-analysis and found that a genetic variant (rs2071287) in NOTCH4 was significantly associated with schizophrenia (a total of 125 848 subjects, p=8.31x10(-17)), with the same risk allele across all tested samples. Expression quantitative trait loci (eQTL) analysis showed that rs2071287 was significantly associated with NOTCH4 expression (p=1.08x10(-14)) in human brain tissues, suggesting that rs2071287 may confer schizophrenia risk through regulating NOTCH4 expression. Sherlock integrative analysis using a large-scale schizophrenia GWAS and eQTL data from human brain tissues further revealed that NOTCH4 was significantly associated with schizophrenia (p=4.03x10(-7) in CMC dataset and p=3.06x10(-6) in xQTL dataset), implying that genetic variants confer schizophrenia risk through modulating NOTCH4 expression. Consistently, we found that NOTCH4 was significantly downregulated in brains of schizophrenia patients compared with controls (p=2.53x10(-3)), further suggesting that dysregulation of NOTCH4 may have a role in schizophrenia. Finally, we showed that NOTCH4 regulates proliferation, self-renewal, differentiation and migration of neural stem cells, suggesting that NOTCH4 may confer schizophrenia risk through affecting neurodevelopment. Our study provides convergent lines of evidence that support the involvement of NOTCH4 in schizophrenia. In addition, our study also elucidates a possible mechanism for the role of NOTCH4 in schizophrenia pathogenesis.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13337
专题	科研部门_神经系统疾病（罗雄剑）
推荐引用方式 GB/T 7714	Zhang, Y,Li, SW,Li, XY,et al. Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene[J]. JOURNAL OF MEDICAL GENETICS,2021,58(10):666-678.
APA	Zhang, Y.,Li, SW.,Li, XY.,Yang, YF.,Li, WQ.,...&Luo, XJ.(2021).Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene.JOURNAL OF MEDICAL GENETICS,58(10),666-678.
MLA	Zhang, Y,et al."Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene".JOURNAL OF MEDICAL GENETICS 58.10(2021):666-678.

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
2023032119.pdf（8958KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文