Informatics Algorithms for Genomic Analysis of Brain Imaging Data

项目概要 脑成像遗传学研究遗传变异与脑成像定量之间的关系 性状（QT）并为揭示神经生物学系统的遗传基础提供了巨大的潜力 可以影响复杂大脑的诊断、治疗和预防方法的发展 失调。限制脑成像遗传学进展的两个关键差距包括（1）前所未有的规模 和成像遗传数据集的复杂性，以及（2）缺乏中级组学数据来捕获 将遗传学与大脑 QT 联系起来的分子效应。我们之前的研究为解决这一问题做出了重大贡献 第一个缺口。拟议的项目将制定新的信息学战略来弥补第二个差距，其中 将利用组学领域有价值的现有数据将大脑成像和遗传学联系起来。在这个项目中， 我们将专注于转录组学，并将利用主要的转录组学数据存储库，包括 基因型组织表达 (GTEx) 项目、英国脑表达联盟 (UKBEC) 和 Allen Human 脑图谱（AHBA）。我们的首要目标是通过证据确定大脑成像遗传关联 表现在人脑转录组中。我们的假设是，有了额外的证据来源 在转录组水平上，所确定的脑成像遗传关联在生物学上更有意义且更少 可能是误报。为了实现我们的目标，我们提出四个目标。目标 1 是开发新型双多元 结合区域组织特异性表达数量性状基因座 (eQTL) 知识进行挖掘的模型 脑成像遗传关联。鉴于 eQTL 是连接基因型的组织特异性证据的来源， 基因表达和大脑 QT，我们将开发新型 eQTL 引导的双多元模型来识别成像 区域组织特异性 eQTL 知识可能证明遗传关联。目标2是发展 结合全脑全基因组（BWGW）跨域共表达的新型双多元模型 挖掘大脑成像遗传学关联的模式。 AHBA，BWGW 基因表达数据库，是一个 基因组和大脑之间的自然联系。我们建议开发新颖的双聚类和双多元 识别具有跨域共表达模式的有意义的 AHBA 模块的方法，并使用这些方法 指导搜索遗传变异和多模式之间的共表达感知关联的模式 脑成像测量。目标 3 是开发用于大脑结构感知挖掘的开源软件工具 成像遗传关联。目标 4 是对模拟数据和真实数据进行评估和验证 成像遗传学队列。成功完成上述目标将产生创新的信息学 对成像、遗传学和转录组学数据进行综合分析的方法和工具，以解决关键问题 脑成像遗传学障碍。使用 ADNI 和相关队列作为试验台，这些方法和工具将 被证明在理解阿尔茨海默病的分子机制方面具有巨大的潜力，并且 预计将影响一般的神经学和精神病学研究，并有益于公共卫生结果。

Project Summary Brain imaging genetics studies the relationship between genetic variations and brain imaging quantitative traits (QTs) and offers enormous potential to reveal the genetic underpinning of the neurobiological system that can impact the development of diagnostic, therapeutic and preventative approaches for complex brain disorders. Two critical gaps limiting the progress of brain imaging genetics include (1) the unprecedented scale and complexity of the imaging genetic data sets, and (2) lack of intermediate-level omics data to capture the molecular effects linking genetics to brain QTs. Our prior studies have contributed substantially to addressing the first gap. The proposed project will develop new informatics strategies to bridge the second gap, where valuable existing data in the omics domain will be leveraged to link brain imaging and genetics. In this project, we will focus on transcriptomics, and will make use of major transcriptomics data repositories including Genotype-Tissue Expression (GTEx) Project, UK Brain Expression Consortium (UKBEC), and Allen Human Brain Atlas (AHBA). Our overarching goal is to identify brain imaging genetic associations with evidence manifested in the human brain transcriptome. Our hypothesis is that, with additional source of evidence at the transcriptomic level, the identified brain imaging genetic associations are biologically more meaningful and less likely to be false positives. To achieve our goal, we propose four aims. Aim 1 is to develop novel bi-multivariate models incorporating regional tissue-specific expression quantitative trait locus (eQTL) knowledge for mining brain imaging genetic associations. Given that eQTL is a source of tissue-specific evidence to link genotype, gene expression, and brain QTs, we will develop novel eQTL-guided bi-multivariate models to identify imaging genetic associations potentially evidenced by regional tissue-specific eQTL knowledge. Aim 2 is to develop novel bi-multivariate models incorporating brain-wide genome-wide (BWGW) cross-domain co-expression patterns for mining brain imaging genetics associations. AHBA, a BWGW gene expression database, is a natural connection between genome and brain. We propose to develop novel biclustering and bi-multivariate methods to identify meaningful AHBA modules with cross-domain co-expression patterns, and use these patterns to guide the search for co-expression-aware associations between genetic variations and multimodal brain imaging measures. Aim 3 is to develop open source software tools for structure-aware mining of brain imaging genetic associations. Aim 4 is to perform evaluation and validation on both simulated data and real imaging genetics cohorts. Successful completion of the above aims will produce innovative informatics methods and tools for integrative analysis of imaging, genetics and transcriptomics data to address a critical barrier in brain imaging genetics. Using ADNI and related cohorts as test beds, these methods and tools will be shown to have considerable potential for understanding the molecular mechanism of Alzheimer’s disease, and be expected to impact neurological and psychiatric research in general and benefit public health outcomes.