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

项目摘要/摘要 吸毒、酗酒和成瘾是可遗传的表型，是导致 世界范围内的发病率和死亡率。现在已有数百个基因座与 药物使用和成瘾的风险，还有更多的基因有待发现。 对有效的稀有遗传变异的研究正在加速我们对基因的理解 复杂疾病的影响和产生引人注目的干预目标 研究和药物开发。目前的提案提供了一个框架，通过这个框架 罕见的变异可以在人类身上有效地识别和评估它们对 使用大量且随时可用的数据集上瘾。此类数据集通常具有稀疏性 表型表型，尤指行为和精神表型。我们的建议 框架通过重新联系和重新评估Rare来克服这一挑战 变异携带者及其家庭成员，允许测量精神疾病 表型远远超出生物库中的可用表型。我们充分利用了 多学科团队，先进的基因组技术，多样化的分析方法， 并对一个大家庭样本进行了详细的深层表型评价。我们 将使用大型的高性能GWAS和全基因组测序数据集来识别 物质使用相关基因内罕见的怀疑有害的变异。vt.在.的基础上 在细胞系中罕见的有害变体的功能验证，我们将使用一种新的 将这些变异基因注入密歇根基因组学倡议生物库的程序， 从而识别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的和量身定做的评估 物质使用/依赖史、精神病史、神经认知史和社会心理史 功能。提出的框架提供了一种新的方法来研究人类 GWAHITS背后的生物学，识别治疗靶点和改善我们的 对成瘾的病因的理解。

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.