Computational Discovery of Synergistic Mechanisms Responsible for Psychiatric Dis

描述(申请人提供)：导致精神障碍的生物学机制在很大程度上是未知的。鉴于识别显著的个体风险遗传变异的成功有限，人们相信，在复杂途径中反映分子元件的多个遗传变异之间负责任的上位性相互作用的发现将阐明新的疾病机制。我们将开展我们的研究，旨在通过我们的计算实验室和基因实验室之间的合作来发现这种机制。我们将开发基于系统的计算和可视化工具来发现这种相互作用，并将它们应用于公共可用的以及内部的两种疾病的全基因组关联数据：精神分裂症和双相情感障碍。我们将验证我们的结果的统计意义，并在独立数据上用电子计算机复制它们。我们的计算方法将被设计用来分析单核苷酸多态(SNPs)以及拷贝数变异(CNV)，使用定量测量一对遗传变异所固有的协同作用，表明可能共同参与了通路。我们将对由此产生的计算输出进行生物学解释，并尝试从基因上验证已识别的相互作用。如果由此产生的涉及两个基因的生物学假说被认为是有希望的，我们将使用体外神经生物学实验来测试这些假说。如果积累了足够的证据来支持生物上位性的可能性，我们最终将在可行的情况下使用遗传学或药理学方法为相互作用对中的一个或两个基因产生转基因动物模型，旨在确认生物相互作用并剖析潜在的机制基础。我们拟议的研究与公共卫生的相关性得到了证明，它有可能增强我们对精神分裂症和双相情感障碍的病因机制的理解。反过来，这些发现将有助于开发这些疾病亟需的诊断和治疗方法。

DESCRIPTION (provided by applicant): The biological mechanisms responsible for psychiatric disorders are largely unknown. Given the limited success of identifying significant individual risk conferring genetic variants, it is believed that discovery of responsible epistatic interactions among multiple genetic variants reflecting molecular elements in complex pathways will elucidate novel disease mechanisms. We will perform our research aimed at discovering such mechanisms through collaboration between our computational and genetic laboratories. We will develop systems-based computational and visual tools to discover such interactions and apply them to publically available as well as in-house genome-wide association data for two diseases: schizophrenia and bipolar disorder. We will validate the statistical significance of our results and replicate them in silico on independent data. Our computational methodology will be designed to analyze both single nucleotide polymorphisms (SNPs) as well as copy number variations (CNVs) using quantitative measures of the synergy inherent in pairs of genetic variants indicating possible joint involvement in pathways. We will biologically interpret the resulting computational outputs and attempt to genetically validate the identified interactions. If the resulting biological hypotheses involving two genes are deemed promising, we will test those using in vitro neurobiological experiments. If enough evidence is accrued to support the possibility of biological epistasis, we will eventually generate transgenic animal models for either one or both genes in an interacting pair using genetic or pharmacological approaches when feasible, designed to confirm a biological interaction and dissect the underlying mechanistic basis. The relevance of our proposed research to public health is evidenced by its potential to enhance our understanding of etiological mechanisms responsible for schizophrenia and bipolar disorder. In turn, these discoveries will be helpful for the development of highly needed diagnostic and therapeutic methods for these diseases.