SZ-associated loci: Functional consequences and treatment opportunities

正常发育和健康生活是基因网络协调功能的结果， 根据需要适当调整他们的平衡。功能性遗传变异可以改变网络平衡和 在不利的情况下，使网络出现故障，导致疾病。最常见的功能遗传 变种在生物体水平上的影响很小，但我们和其他人的数据表明，它们可能有 在缺乏有机体缓冲防御机制的情况下，对分离的细胞的影响要大得多。在单元格中 变化可能更显著，最直接的变化是细胞的转录输出。这个 功能变体的转录签名反映了它破坏的特定网络，并在研究时 跨越许多变种可以帮助确定干预目标。我们建议研究10个SZ相关基因座和 通过以下具体措施确定它们的共同网络和候选药理干预措施 目标：1)我们将选择一个或几个实验就能自信地实现靶向功能的基因座 变种。我们将编辑一男一女诱导多能干细胞(IPSC)的基因组，以 为风险等位基因和非风险等位基因生成纯合子。这些将成为实现下一个目标和 与他人分享。2)我们将IPSC区分为皮质神经元和星形胶质细胞，并比较 这两个纯合子的转录本在其他方面是相同的。我们将执行20个特定的基因座 每种细胞类型的转录组分析(雄性细胞10个，雌性细胞10个)，并比较结果。3)我们会 一起分析所有的基因座，以确定类似地改变其表达的基因簇 修改过的基因座。我们将执行探索性分析，以深入了解这些集群的参与情况 在疾病风险方面，最好的跟踪候选分类以及每个分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签名进行第一次筛查，如下所示 向上选择化合物以验证神经元和星形胶质细胞的互补性，测试SZ变体的挽救 引起的变化，并确定可能的性别差异。在项目结束时，我们将创建 携带功能确认的SZ风险等位基因的修饰iPS细胞的第一个来源。我们将会确认 基因簇反映了许多SZ基因座共有的网络中断的特征。我们将会确定 特异度每个簇都对疾病表型和确定的候选药理有贡献 用于进一步测试的干预措施。

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.