Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
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DOI：
10.1101/052209
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发表时间：
2016-05
影响因子：
25
通讯作者：
M. Fromer;P. Roussos;S. Sieberts;Jessica S. Johnson;D. Kavanagh;T. Perumal;D. Ruderfer;Edwin C. T. Oh-E
中科院分区：
文献类型：
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作者：
M. Fromer;P. Roussos;S. Sieberts;Jessica S. Johnson;D. Kavanagh;T. Perumal;D. Ruderfer;Edwin C. T. Oh-E
超过100个基因位点存在与精神分裂症相关的变异，然而这些变异如何赋予责任尚不确定。CommonMind联盟对258名精神分裂症患者和279名对照组的背外侧前额叶皮层的RNA进行了测序，创建了基因表达及其遗传调控的资源。利用这一资源，约20%的精神分裂症基因座具有可能导致基因表达和倾向性改变的变异。在五个位点中，只有一个基因参与：FURIN、TSNARE1、CNTN4、CLCN3或SNAP91。改变FURIN、TSNARE1或CNTN4的表达可改变斑马鱼的神经发育在人神经祖细胞中敲低FURIN会产生异常迁移。在693个表现出显著病例与对照差异表达的基因中，它们的折叠变化≤1.33，独立队列也得出了类似的结果。基因共表达暗示了一个与精神分裂症相关的网络。我们的研究结果表明，精神分裂症是多基因的，并强调了这种资源对脑部疾病遗传倾向的机制解释的效用。
Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.