Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production
Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production
复制标题
miR-338-3p 导致精神分裂症相关的 rs4702 G 等位基因特异性下调 FURIN 表达，从而减少 BDNF 的产生
DOI：
10.1016/j.schres.2018.02.040
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发表时间：
2018-09-01
影响因子：
4.5
通讯作者：
Zhao, Cunyou
中科院分区：
文献类型：
--
作者：
Hou, Yu;Liang, Wenquan;Zhao, Cunyou
全基因组关联研究（GWAS）揭示了许多与精神分裂症（SCZ）相关的单核苷酸多态性（SNP）;然而，风险变体的功能特征仍有待建立。利用来自108个SCZ GWAS位点的数据，我们对128个SCZ相关SNP进行了系统的miRNA结合位点筛选，发现位于3 'UTR的3个SNP中有2个被预测改变了2个靶基因中3个miRNA的结合位点。在所鉴定的SNP中，FURIN 3 'UTR中最具全基因组显著性的SNP rs 4702（A/G），先前被鉴定为SCZ相关顺式表达数量性状基因座（被风险G等位基因下调），在风险G等位基因存在下位于miR-338- 3 p的结合位点。用荧光素酶报告基因测定验证了miR-338- 3 p对FURIN的等位基因特异性下调。此外，我们证明了miR-338- 3 p介导的FURIN抑制减少了人胚肾293 T细胞中脑源性神经营养因子（BDNF）的成熟和分泌。我们的数据表明，精神分裂症相关的rs 4702 G等位基因特异性下调FURIN的miR-338- 3 p减少成熟的BDNF的生产。这些数据有助于阐明精神分裂症或其他神经发育疾病的遗传易感性机制。(c)2018爱思唯尔B. V.保留所有权利。
Genome-wide association studies (GWAS) reveal numerous schizophrenia (SCZ)-associated single-nucleotide polymorphisms (SNPs); however, functional characterizations of the risk variants remain to be established. Using data from 108 SCZ GWAS loci, we performed systematic miRNA binding site screening of 128 SCZ-associated SNPs and found that 2 out of 3 SNPs located in the 3'UTR were predicted to alter 3 miRNAs' binding sites in 2 target genes. Of the identified SNPs, the most genome-wide significant SNP rs4702 (A/G) in the FURIN 3'UTR, previously identified as an SCZ-associated cis-expression quantitative trait loci (downregulated by the risk G allele), is located in the binding site of miR-338-3p in the presence of the risk G allele. Allele-specific downregulation of FURIN by miR-338-3p was validated with a luciferase reporter assay. Furthermore, we demonstrated that miR-338-3p-mediated FURIN inhibition reduced brain-derived neurotrophic factor (BDNF) maturation and secretion in human embryonic kidney 293T cells. Our data reveal that schizophrenia-associated rs4702 G allele-specific downregulation of FURIN by miR-338-3p reduces mature BDNF production. These data help elucidate the mechanism of genetic predisposition toward schizophrenia or other neurodevelopmental diseases. (c) 2018 Elsevier B.V. All rights reserved.