Integrative Omics Center for Accelerating Neurobiological Understanding of Opioid Addiction (ICAN)

项目摘要/摘要 综合全基因组学中心的首要目标是促进对神经生物学的理解 阿片成瘾(ICAN)是为了确定阿片成瘾(OA)的生物可操作的驱动因素。我们将(1) 进行人类骨性关节炎的大规模综合多组学研究；(2)整合啮齿动物-人类研究以 确定与骨质疏松症有关的基因和基因网络，以及(3)建立公开可用的国家组学资源 学习办公自动化。我们的凝聚原则是通过整合人类和动物模型中的多个组学 数据我们将发现个体变异的强大驱动因素，使阿片类药物使用者容易上瘾。 组学革命为复杂疾病带来了许多个体差异的发现， 包括尼古丁和酒精的表型，但不包括OA。我们看到了快速发展面临的五大基本挑战 进展：(1)有限的样本量和全基因组的表型异质性 骨质疏松症的关联研究；(2)对骨质疏松症基因失调的人脑研究非常有限；(3) 人类和动物模型研究之间的翻译不佳；(4)缺乏多个 组学；以及(5)对办公自动化组学数据的实际获取有限，协调不力。 为了克服这些挑战，ICAN利用四个项目和两个核心： 项目1：阿片成瘾的电子健康记录表型和基因组学 项目2：阿片依赖人脑中的基因调控 项目3：对阿片成瘾采取多物种办法 项目4：多组学基因网络鉴定 核心：管理核心和协同核心 在这些项目和核心中，我们将(1)开展迄今规模最大的全球气候变化(N&GT；100,000个案例) 利用基因组结构方程模型；(2)检验关键大脑的差异基因调控 前额叶皮质、伏隔核、杏仁核是OA信息量最大的区域 迄今的死后脑研究(N=641)；(3)使用GeneWever.org整合啮齿动物和人类的研究， 多基因转录组风险评分和变异功能实验；以及(4)应用可解释的 人工智能、基因网络作图和基因网络的多条证据线整合 发现号。每个项目都经过了严格的设计，以做出新的贡献。但是，通过集成 通过各核心部门的相互促进和协调努力，我们将 利用组学的不可知性发现能力，并将其置于功能神经生物学的背景下 取得改变领域的突破，并确定可操作的目标，以开发OA治疗方法。

PROJECT SUMMARY/ABSTRACT The overarching goal of the Integrative Omics Center for Accelerating Neurobiological Understanding of Opioid Addiction (ICAN) is to identify biologically actionable drivers of opioid addiction (OA). We will (1) conduct large-scale integrated multi-omics studies of OA in humans, (2) integrate rodent–human studies to identify genes and gene networks implicated in OA, and (3) build a publicly available national omics resource for studying OA. Our cohering principle is that by integrating multiple omics across human and animal model data we will discover robust drivers of individual variation that predispose opioid users to addiction. The omics revolution has delivered many discoveries of such individual variation for complex diseases, including for nicotine and alcohol phenotypes, but not for OA. We see five fundamental challenges to rapid progress: (1) limited sample sizes and unaccounted-for phenotypic heterogeneity in genome-wide association studies (GWAS) of OA; (2) very limited human brain studies of gene dysregulation by OA; (3) poor translation between human and animal model studies; (4) lack of concurrent integration of multiple omics; and (5) limited practical access to, and poor harmonization of, OA omics data. To overcome these challenges, ICAN harnesses four Projects and two Cores: Project 1: Electronic Health Record Phenotyping and Genomics of Opioid Addiction Project 2: Gene Regulation in the Opioid Dependent Human Brain Project 3: Multi-species Approach to Opioid Addiction Project 4: Multi-omics Gene Network Identification Cores: Administrative Core and Synergy Core Across these Projects and Cores, we will (1) conduct the largest GWAS to date (N>100,000 cases) leveraging Genomic Structural Equation Modeling; (2) examine differential gene regulation across key brain regions (prefrontal cortex, nucleus accumbens, amygdala) in the largest collection of OA informative postmortem brains to date (N=641); (3) integrate rodent and human studies using GeneWeaver.org, polygenic transcriptome risk scores, and variant functionalizing experiments; and (4) apply explainable artificial intelligence, gene network mapping, and multiple lines-of-evidence integration for gene network discovery. Each Project is rigorously designed to make novel contributions. However, by integrating the diversity of ICAN’s science through the cross-fertilization and coordinating efforts of the Cores, we will leverage the agnostic discovery power of omics and place it within the context of functional neurobiology to make field-changing breakthroughs and identify actionable targets for development of OA treatments.