Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia

项目摘要 精神分裂症(SCZ)基因组学取得了前所未有的进展。十年前，可能有一个 可靠的发现，现在大约有270个基因座符合普遍的重要性和重复性标准。AS 对于其他复杂的精神障碍，所识别的区域绝大多数是非编码的， 有力地表明，基因调控元件的遗传变异是一个主要的机制贡献因素。 对这些监管机制的进一步调查是由于在能力上的根本差距 确定、表征和量化与大脑相关的监管要素，以及对如何 这些元素中的遗传变异会影响它们的功能。 为了解决这一知识差距，该项目将全面确定、表征、量化和验证 神经细胞中的非编码功能非编码调控元件和变体。的中心假说 研究认为，非编码变异通过直接改变细胞的功能而导致精神障碍。 大脑中的调控元素。拟议研究的动机是确定监管机构 精神障碍的机制有可能转化为更好的诊断和治疗。 由一支在精神障碍、功能基因组学、 技术发展和统计遗传学，这一假说将通过完成三个具体的 目标：1)全面集成不同的数据类型，以生成“连接”的假设 特定基因的精神病学遗传结果；2)执行高通量CRISPR表观基因组编辑 筛选以在自然生物学环境中测试目标1假设；3)发展机械理解和 使用TF结合分析和来自SCZ的iPS来源的神经元验证SCZ风险变异体的非编码功能 遗传风险分数高的病例。 我们的方法是创新的，因为它使用了一套高度互补和多样化的实验 推动对与SCZ相关的调控机制进行有针对性的遗传和功能调查的方法。 在这样做的过程中，拟议的研究提供了一条亟需的前进道路，以了解非编码是如何 变异导致了复杂的人类表型。

Project Summary Schizophrenia (SCZ) genomics has achieved unprecedented advances. A decade ago, there was perhaps one solid finding, and there are now ~270 loci that meet consensus criteria for significance and replication. As observed for other complex psychiatric disorders, the identified regions are overwhelmingly noncoding, strongly suggesting that genetic variation in gene regulatory elements is a major mechanistic contributor. Further investigation of those regulatory mechanisms is precluded by a fundamental gap in the ability to identify, characterize, and quantify brain-relevant regulatory elements, and limited understanding of how genetic variation within those elements influences their function. To address this knowledge gap, this project will comprehensively identify, characterize, quantify, and validate noncoding functional noncoding regulatory elements and variants in neuronal cells. The central hypothesis of the proposal is that noncoding variation contributes to psychiatric disorders by directly altering the function of regulatory elements in the brain. The motivation for the proposed study is that identifying regulatory mechanisms of psychiatric disorders has the potential to translate into improved diagnosis and treatment. Powered by a team with strong interdisciplinary expertise in psychiatric disorders, functional genomics, technology development, and statistical genetics, this hypothesis will be tested by completing three specific aims: 1) Comprehensive integration of diverse data types to generate hypotheses that “connect” psychiatric genetic results to specific genes; 2) perform high-throughput CRISPR epigenome editing screens to test Aim 1 hypotheses in a natural biological context; 3) Develop mechanistic understanding and validate functional noncoding SCZ risk variants using TF binding assays and iPS-derived neurons from SCZ cases with high genetic risk scores. Our approach is innovative because it uses a highly complementary and diverse set of experimental approaches to drive targeted genetic and functional investigation into regulatory mechanisms relevant for SCZ. In doing so, the proposed research provides a much-needed path forward to understand how noncoding variation contributes to complex human phenotypes.