Collaborative Research - Combining Heterogeneous Data Sources to Identify Genetic Modifiers of Diseases

了解人类疾病的原因和寻找治疗方法的最重要方法之一是研究人类遗传学。全基因组关联研究（GWAS）已被用于确定与常见疾病和失调相关的基因组区域。然而，通过这些方法确定的遗传变异通常只能解释其已知遗传力的一小部分，并且在发现致病变异方面的记录很差。该项目将开发工具，将GWAS与其他数据来源结合起来，例如识别重要罕见变异的基于家族的遗传研究，以及捕获疾病中基因表达特征的转录组学或蛋白质组学研究，以发现单独使用GWAS可能完全遗漏的遗传修饰因子。该项目将通过结合不同实验类型的信息来确定与疾病进展有关的基因。将采用的统计模型家族的基本组成部分是一个分层的三组混合分布。每个基因的概率模型要么属于与疾病进展无关的零组，要么属于与负面疾病结果相关的有害组，要么属于与积极疾病结果相关的有益组。这种三组形式论有两个关键特征。首先，通过用狄利克雷分布分配群体分配的先验概率，得到的后验群体概率自动考虑了同时分析多个基因所固有的多样性。其次，通过在组标签上有条件地建立实验结果模型，任何数量的数据模式都可以组合在一个连贯的概率模型中，从而允许跨实验类型的信息共享。这两个特点使得推理简洁，误报少，同时提高了检测信号的能力。应用联合分析方法的模型疾病将是帕金森病。疾病（PD）。PD和对照患者的基因组序列将与公共来源的转录组数据和靶向单核苷酸多态性（SNP）阵列数据一起进行分析。此外，一种称为机器人显微镜（RM）的强大成像方法将用于功能性评估统计模型的预测，从而为模型提供实验反馈。使用PD患者诱导的多能干细胞（i-神经元）和RM衍生的人类神经元，PD i-神经元中预测有益或有害的基因水平将被调节，疾病表型的缓解或加剧将被量化，以验证或无效统计模型的预测。使用三组框架结合基因组、转录组、表型和潜在的其他信息源的策略可应用于具有多种可用数据类型的任何遗传性疾病。该项目的分析方法将有助于确定哪些基因可能在发病机制中发挥作用，从而产生治疗靶点和潜在的个性化“精准医学”。这可能会直接导致PD的治疗，此外还可以为其他研究人员寻求其他遗传性疾病的治疗提供一套有用的工具。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

One of the most important approaches to understanding the causes and finding treatments for human disease is the study of human genetics. Genome Wide Association Studies (GWAS) have been used to identify regions of the genome associated with common diseases and disorders. However, genetic variants identified through these approaches usually explain only a small fraction of their known heritability and have yielded a poor record of finding disease-causing variants. This project will develop tools to combine GWAS with other sources of data, such as family-based genetic studies that identify important rare variants and transcriptomic or proteomic studies that capture gene expression signatures in disease, to find genetic modifiers that would be entirely missed using GWAS alone.This project will identify genes involved in disease progression by combining information across different experimental types. The fundamental building block of the family of statistical models that will be employed is a hierarchical three-group mixture of distributions. Each gene is modeled probabilistically as belonging to either a null group that is unassociated with disease progression, a deleterious group that is associated with negative disease outcomes, or a beneficial group that is associated with positive disease outcomes. This three-group formalism has two key features. First, by apportioning prior probability of group assignments with a Dirichlet distribution, the resultant posterior group probabilities automatically account for the multiplicity inherent in analyzing many genes simultaneously. Second, by building models for experimental outcomes conditionally on the group labels, any number of data modalities may be combined in a single coherent probability model, allowing information sharing across experiment types. These two features result in parsimonious inference with few false positives, while simultaneously enhancing power to detect signals. The model disease for applying the combined analysis approach will be Parkinson?s Disease (PD). Genomic sequences from PD and control patients will be jointly analyzed along with transcriptomic data from public sources and targeted single nucleotide polymorphism (SNP) array data. In addition, a powerful imaging approach called robotic microscopy (RM) will be used to functionally evaluate the predictions of the statistical model thereby providing experimental feedback to the model. Using human neurons derived from PD patient induced pluripotent stem cells (i-neurons) and RM, levels of genes predicted to be beneficial or deleterious will be modulated in the PD i-neurons, and mitigation or exacerbation of disease phenotypes will be quantified to validate or invalidate predictions of the statistical model. The strategy of combining genomic, transcriptomic, phenotypic, and potentially other sources of information using the three-groups framework can be applied to any heritable disease with multiple data types available. The analytical approach in this project will help identify which genes are likely to play a role in pathogenesis, resulting in therapeutic targets and potentially individualized "precision medicine". This could lead directly to treatments for PD, and in addition could provide a useful set of tools for other researchers to pursue therapies for other heritable diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.