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）遗传学的理解正在快速发展。越来越多的风险相关的多态性和变异被发现，其中许多位于基因间，内含子和其他非编码序列。一个主要的挑战在于设计可验证的假设，以阐明疾病相关的非编码DNA的潜在功能。这些序列中的许多被认为发挥调节功能，包括与沿着线性基因组沿着分开的转录起始位点物理相互作用的长距离增强子元件，有时被许多DNA内切酶分开。该提议旨在产生源自与BD的病理生理学相关的两个人类皮质脑区域的离散细胞群体（神经元和神经胶质）中的开放染色质的高分辨率数量性状基因座（QTL）图谱。然后，我们将利用高分辨率表达数量性状基因座（eQTL），映射在相同的样品和大脑区域，以确定BD相关的非编码区，同时与差异暴露的调控区（开放染色质）和基因表达附近的基因（eQTL）。长距离增强子-启动子相互作用的基因可能受到开放的染色质序列的调控，将映射在人类死后的脑组织中使用染色体构象捕获，在神经表观遗传学的创新方法。将基于现有的BD相关大规模分子数据和通过拟议研究生成的高影响力、高分辨率、补充数据集开发与BD有因果关系的多尺度网络模型。使用iPS细胞衍生的人类神经元细胞系统的培养物，我们将采用高通量分子和细胞筛选测定，不仅验证单个基因对分子和细胞BD相关过程的作用，而且验证我们研究中鉴定的分子网络。这里提出的多维方法提供了一个路线图，将BD遗传风险变异的分子背景下，以帮助确定潜在的监管和表达机制，通过它们的行为。作为对BD研究社区的服务，我们将提供对大规模多维数据集的显着改进的一般访问，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.