Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
Sci Transl Med. 2018 Dec 19;10(472). doi: 10.1126/scitranslmed.aat6912. Epub 2018 Dec 13.
A number of studies indicate that rare copy number variations (CNVs) contribute to the risk of schizophrenia (SCZ). Most of these studies have focused on protein-coding genes residing in the CNVs. Here, we investigated long noncoding RNAs (lncRNAs) within 10 SCZ risk-associated CNV deletion regions (CNV-lncRNAs) and examined their potential contribution to SCZ risk. We used RNA sequencing transcriptome data derived from postmortem brain tissue from control individuals without psychiatric disease as part of the PsychENCODE BrainGVEX and Developmental Capstone projects. We carried out weighted gene coexpression network analysis to identify protein-coding genes coexpressed with CNV-lncRNAs in the human brain. We identified one neuronal function-related coexpression module shared by both datasets. This module contained a lncRNA called within the 22q11.2 CNV region, which was identified as a hub gene. Protein-coding genes associated with SCZ genome-wide association study signals, de novo mutations, or differential expression were also contained in this neuronal module. Using knockdown and overexpression experiments in human neural progenitor cells derived from human induced pluripotent stem cells, we identified a potential role for in regulating certain SCZ-related genes.
一些研究表明,罕见的拷贝数变异(CNVs)会增加精神分裂症(SCZ)的风险。这些研究大多集中在位于 CNVs 中的编码蛋白的基因上。在这里,我们研究了 10 个与 SCZ 风险相关的 CNV 缺失区域(CNV-lncRNAs)中的长非编码 RNA(lncRNAs),并检查了它们对 SCZ 风险的潜在贡献。我们使用了来自没有精神疾病的对照个体死后脑组织的 RNA 测序转录组数据,这些数据是 PsychENCODE BrainGVEX 和发育性顶点项目的一部分。我们进行了加权基因共表达网络分析,以鉴定与人类大脑中 CNV-lncRNAs 共表达的编码蛋白基因。我们确定了两个数据集共有的一个与神经元功能相关的共表达模块。该模块包含位于 22q11.2 CNV 区域的一个 lncRNA,称为 ,它被鉴定为一个枢纽基因。与 SCZ 全基因组关联研究信号、新生突变或差异表达相关的编码蛋白基因也包含在这个神经元模块中。在源自人诱导多能干细胞的人神经祖细胞中使用 敲低和过表达实验,我们鉴定了 在调节某些与 SCZ 相关基因中的潜在作用。