Regulatory mechanisms of major depressive disorder risk variants

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	Regulatory mechanisms of major depressive disorder risk variants
	Li, Shiwu; Li, Yifan; Li, Xiaoyan; Liu, Jiewei; Huo, Yongxia; Wang, Junyang; Liu, Zhongchun; Li, Ming; Luo, Xiong-Jian
	2020
发表期刊	MOLECULAR PSYCHIATRY
ISSN	1359-4184
卷号	25 期号:9 页码:1926-1945
摘要	Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Though recent genome-wide association studies (GWAS) have identified multiple risk variants for MDD, how these variants confer MDD risk remains largely unknown. Here we systematically characterize the regulatory mechanism of MDD risk variants using a functional genomics approach. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) (from human brain tissues or neuronal cells) and position weight matrix (PWM) data, we identified 34 MDD risk SNPs that disrupt the binding of 15 transcription factors (TFs). We verified the regulatory effect of the TF binding-disrupting SNPs with reporter gene assays, allelic-specific expression analysis, and CRISPR-Cas9-mediated genome editing. Expression quantitative trait loci (eQTL) analysis identified the target genes that might be regulated by these regulatory risk SNPs. Finally, we found that NEGR1 (regulated by the TF binding-disrupting MDD risk SNP rs3101339) was dysregulated in the brains of MDD cases compared with controls, implying that rs3101339 may confer MDD risk by affecting NEGR1 expression. Our findings reveal how genetic variants contribute to MDD risk by affecting TF binding and gene regulation. More importantly, our study identifies the potential MDD causal variants and their target genes, thus providing pivotal candidates for future mechanistic study and drug development.
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/152453/12913
专题	科研部门_转化基因组（李明）
推荐引用方式 GB/T 7714	Li, Shiwu,Li, Yifan,Li, Xiaoyan,et al. Regulatory mechanisms of major depressive disorder risk variants[J]. MOLECULAR PSYCHIATRY,2020,25(9):1926-1945.
APA	Li, Shiwu.,Li, Yifan.,Li, Xiaoyan.,Liu, Jiewei.,Huo, Yongxia.,...&Luo, Xiong-Jian.(2020).Regulatory mechanisms of major depressive disorder risk variants.MOLECULAR PSYCHIATRY,25(9),1926-1945.
MLA	Li, Shiwu,et al."Regulatory mechanisms of major depressive disorder risk variants".MOLECULAR PSYCHIATRY 25.9(2020):1926-1945.

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2021110103.pdf（6968KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文