Risk genetic variants and cis regulation of gene expression in Bipolar Disorder

 描述(由申请人提供)：我们对双相情感障碍(BD)的遗传学的了解正在快速发展。越来越多的与风险相关的多态和变异被发现，其中许多存在于基因间、内含子和其他非编码序列中。一个主要的挑战在于设计可测试的假说来阐明与疾病相关的非编码DNA的潜在功能。这些序列中的许多被认为具有调节功能，包括与沿着线性基因组分开的转录起始点物理上相互作用的长程增强子元件，有时是许多千碱基的DNA。这项建议旨在建立一个高分辨率的数量性状基因座(QTL)的开放染色质的离散细胞群体(神经元和神经胶质细胞)来自两个与BD病理生理学相关的人类大脑皮质区域。然后，我们将利用在相同样本和大脑区域定位的高分辨率表达数量性状基因座(EQTL)来识别与BD相关的非编码区，这些非编码区同时与调节区(开放染色质)的差异暴露和邻近基因的基因表达(EQTL)相关。利用神经表观遗传学中的一种创新方法-染色体构象捕捉，可能受开放染色质序列调控的基因的长程增强子-启动子相互作用将在人类死后脑组织中定位。与BD因果关联的多尺度网络模型将基于现有的BD相关的大规模分子数据和通过拟议的研究产生的高影响、高分辨率、互补的数据集而开发。使用iPS细胞来源的人类神经细胞系统的培养，我们将使用高通量的分子和细胞筛选分析，不仅验证单个基因在分子和细胞BD相关过程中的作用，而且验证我们研究中确定的分子网络。这里提出的多维方法提供了一个路线图，将BD遗传风险变异放在分子环境中，以帮助确定它们发挥作用的潜在调控和表达机制。作为对BD研究社区的一项服务，我们将极大地改进对大规模、多维数据集的一般访问，以及对这些数据集的系统级分析。

 DESCRIPTION (provided by applicant): Our understanding of the genetics of bipolar disorder (BD) is advancing at a rapid pace. An increasing number of risk-associated polymorphisms and variants are being found, many of which reside in intergenic, intronic and other non-coding sequences. A major challenge lies in designing testable hypotheses to elucidate the potential function of disease-associated non-coding DNA. Many of these sequences are thought to exert regulatory functions, including long-range enhancer elements physically interacting with transcription start sites separated along the linear genome, sometimes by many kilobases of DNA. This proposal aims to generate a high- resolution quantitative trait loci (QTL) map of open chromatin in discrete cellular populations (neurons and glia) derived from two human cortical brain regions relevant to the pathophysiology of BD. We will then leverage high resolution expression quantitative trait loci (eQTLs), mapped in the same samples and brain regions, to identify BD associated noncoding regions that are simultaneously associated with differential exposure of regulatory regions (open chromatin) and gene expression of nearby genes (eQTLs). Long-range enhancer- promoter interactions of genes potentially regulated by open chromatin sequences will be mapped in human postmortem brain tissue using chromosome conformation capture, an innovative approach in neuroepigenetics. Multiscale network models causally linked to BD will be developed based on existing BD- related large-scale molecular data and the high-impact, high-resolution, complementary datasets generated through the proposed studies. Using iPS-cell-derived cultures of human neuronal cell systems, we will employ high-throughput molecular and cellular screening assays to not only validate the actions of individual genes on molecular and cellular BD-associated processes, but also to validate the molecular networks identified in our studies. The multidimensional approach presented here provides a roadmap to place BD genetic risk variants in molecular contexts to help identify the underlying regulatory and expression mechanisms through which they act. As a service to the BD research community, we will provide dramatically improved general access to large- scale, multidimensional datasets, together with systems level analyses of these datasets.