Deep Sequencing, Phenotyping, and Imputation in Large-Scale Biobanks: A Novel and Cost-Effective Framework to Identify Rare Mutations Associated with Addiction

项目概要/摘要 药物和酒精的使用和成瘾是遗传表型，是主要的原因， 发病率和死亡率。数百个基因位点与 药物使用和成瘾的风险，还有更多的基因有待发现。 对罕见遗传变异的研究正在加速我们对遗传变异的理解。 复杂疾病的影响，并制定引人注目的干预目标 研究和药物开发。目前的建议提供了一个框架， 罕见的变异可以在人类中有效地鉴定和评估其对 成瘾使用大型和现成的数据集。这样的数据集通常具有稀疏的 表型，特别是行为和精神表型。我们提出的 框架通过重新接触和重新评估罕见的 变异携带者及其家庭成员，允许测量精神疾病 表型远远超出了生物库中的可用表型。我们充分利用 多学科团队，先进的基因组技术，多样化的分析方法， 并对大家族样本进行了详细的深入表型评估。我们 将使用大型高性能GWAS和全基因组测序数据集来识别 物质使用相关基因座内的罕见有害变异。后 为了验证细胞系中罕见的有害变体的功能，我们将使用一种新的 将这些变异输入密歇根基因组学倡议生物库的程序， 从而鉴定罕见有害等位基因的携带者。这些人，以及他们的 家庭，将重新联系，并接受标准和量身定制的评估， 物质使用/依赖史、精神病、神经认知和心理社会 功能所提出的框架提供了一种新的方法来调查人类 GWAS命中的生物学基础，确定治疗靶点并改善我们的 了解成瘾的病因。

Project Summary/Abstract Drug and alcohol use and addiction are heritable phenotypes that are leading causes of morbidity and mortality worldwide. Hundreds of loci have now been strongly linked to risk for substance use and addiction, and many more genes remain to be discovered. Studies of impactful rare genetic variants are accelerating our understanding of genetic influences of complex disease and producing compelling targets for intervention research and drug development. The current proposal provides a framework by which rare variants can be efficiently identified and evaluated in humans for their effects on addiction using large and readily available datasets. Such datasets often have sparse phenotyping, especially for behavioral and psychiatric phenotypes. Our proposed framework overcomes this challenge through re-contact and reassessment of rare variant carriers and their family members, allowing measurement of psychiatric phenotypes far beyond that available in biobanks. We take full advantage of a multidisciplinary team, advanced genomic technology, diverse analytical approaches, and detailed deep phenotypic assessment on a sample of large extended families. We will use large highly-powered GWAS and whole genome sequencing datasets to identify rare putatively deleterious variants within substance-use-associated loci. Upon functional validation of the rare deleterious variant in cell lines, we will use a novel procedure to impute such variants into the Michigan Genomics Initiative Biobank, thereby identifying carriers of rare deleterious alleles. These individuals, and their families, will be re-contacted and receive standard and tailored assessments of their substance use/dependence history, psychiatric, neurocognitive, and psychosocial function. The proposed framework offers a new approach to investigate the human biology underlying GWAS hits, identifying therapeutic targets and improving our understanding of the etiology of addiction.