SZ-associated loci: Functional consequences and treatment opportunities

正常发育和健康生活是基因网络协调作用的结果， 根据需要适当调整其平衡。功能性遗传变异可以改变网络平衡， 在不利的环境下使网络失效，导致疾病。最常见的功能性遗传 变异在生物体水平上的影响很小，然而我们和其他人的数据表明，它们可能具有 在缺乏生物体缓冲防御机制的情况下，对孤立细胞的影响要大得多。细胞中 变化可能更引人注目，最直接的变化是细胞的转录输出。的 功能变体的转录特征反映了它破坏的特定网络， 可以帮助确定干预目标。我们建议研究10个SZ相关位点， 通过以下具体措施确定其共同网络和候选药物干预措施 目的：1）我们将选择一个或几个实验可以自信地实现靶向功能的基因座， 变量。我们将编辑一个男性和一个女性诱导多能干细胞（iPSC）系的基因组， 产生风险和非风险等位基因的纯合子。这些将是下一个目标的资源， 与他人分享。2)我们将iPSc与皮质神经元和星形胶质细胞区分开来，并比较它们之间的差异。 两个纯合子的转录组，否则是等基因的。我们将进行20个特定的位点 每种细胞类型的转录组分析（雄性细胞中10个，雌性细胞中10个）并比较结果。3)我们将 分析所有的基因座，以确定基因簇，类似地改变他们的表达，以响应许多 修饰位点我们将进行探索性分析，可能会提供这些集群的参与见解 在疾病风险中，随访的最佳候选聚类以及每个聚类与临床的具体关系 演示文稿.然后，我们将利用公共资源对补充药物特征进行第一次筛选， 向上选择化合物以验证神经元和星形胶质细胞中的互补性，测试SZ变体的拯救 引起的变化，并确定可能的男女差异。在项目结束时，我们将创建 第一个来源的修饰的iPS细胞携带功能确认SZ风险等位基因。我们会确认 基因簇反映了许多SZ基因座共享的网络中断的签名。我们将确定 特异性每个簇有助于疾病表型和鉴定的候选药理学 进行进一步的测试。

Normal development and healthy life are the result of the coordinated function of gene networks that appropriately adjust their equilibrium as needed. Functional genetic variation can shift network equilibrium and under unfavorable circumstances make networks fail, leading to disease. Most common functional genetic variants have small effects at the organism level, however our and others' data suggest that they may have much larger effects on isolated cells, in the absence of the organism's buffering defense mechanisms. In cells changes can be more striking, the most immediate change being in the cell's transcriptional output. The transcriptional signature of a functional variant reflects the specific networks it disrupts and when studied across many variants can help identify intervention targets. We propose to study 10 SZ associated loci and identify their common networks and candidate pharmacological interventions through the following specific aims: 1) We will choose loci where one or few experiments can confidently achieve targeting the functional variant. We will edit the genome of one male and one female induced pluripotent stem cell (iPSc) line to generate homozygotes for the risk and non-risk allele. These will be a resource for the next aims and for sharing with others. 2) We will differentiate the iPSc to cortical neurons and to astrocytes and compare the transcriptomes of the two homozygotes that are otherwise isogenic. We will perform 20 locus specific transcriptome analyses per cell type (10 in male and 10 in female cells) and compare results. 3) We will analyze all loci together to identify gene clusters that similarly change their expression in response to many modified loci. We will perform exploratory analyses that may offer insights in the involvement of these clusters in disease risk, the best candidate cluster for follow up and the specific relationship of each cluster to clinical presentation. We will then do a first screen for complementary drug signatures utilizing public resources, follow up select compounds to verify complementarity in neurons and astrocytes, test for rescue of the SZ variant induced changes and identify possible male-female differences. At the end of the project we will have created the first resource of modified iPS cells carrying functionally confirmed SZ-risk alleles. We will have identified gene clusters reflecting signatures of network disruptions shared by many SZ loci. We will have determined the specificity each cluster contributes to the disease phenotype and identified candidate pharmacological interventions for further testing.