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

大规模生物库中的深度测序、表型分析和插补：一种新颖且具有成本效益的框架，用于识别与成瘾相关的罕见突变

• 批准号: 10355455
• 负责人: Frank Wolfgang Albert
• 金额: $ 64.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355455
• 关键词: Affect; Alcohol consumption; Alcohol dependence; Alleles; Behavior; Behavioral; Biological; CRISPR/Cas technology; Cell Line; Clinical; Communities; Complementary DNA; Complex; Consent; Data; Data Set; Dependence; Development; Disease; Drug Addiction; Drug usage; Epigenetic Process; Etiology; Extended Family; Family; Family member; Functional disorder; Genes; Genetic; Genomics; Genotype; Haplotypes; Hereditary Disease; Heritability; Human; Human Biology; Individual; Induced Mutation; Intervention Studies; Investigation; Link; Measurement; Medical; Meta-Analysis; Michigan; Molecular; Morbidity - disease rate; Mutation; Neurocognitive; Participant; Pharmaceutical Preparations; Phenotype; Price; Procedures; Recording of previous events; Reporting; Research Personnel; Risk; Sampling; Smoking; Substance Addiction; Technology; Testing; Time; Tobacco use; Trans-Omics for Precision Medicine; Translating; Translational Research; United States National Institutes of Health; Validation; Variant; addiction; base; biobank; bioinformatics tool; case control; cost; cost effective; deep sequencing; design; dosage; drug development; ethnic diversity; experimental study; follow-up; genetic association; genetic pedigree; genetic resource; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic locus; improved; insight; interest; mortality; multidisciplinary; nicotine use; novel; novel strategies; psychosocial; rare variant; recruit; repository; research and development; substance use; therapeutic target; trait; translational potential; variant detection; whole genome

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.

项目摘要/摘要 毒品和饮酒和成瘾是可遗传的表型，是导致原因的主要原因 全球发病率和死亡率。现在有数百个基因座与 物质使用和成瘾的风险，还有更多基因有待发现。 有影响力的稀有遗传变异的研究正在加速我们对遗传的理解 复杂疾病的影响并为干预产生引人注目的目标 研究与药物开发。当前的建议提供了一个框架 可以在人类中有效地识别和评估稀有变体的影响 使用大型且随时可用的数据集成瘾。这样的数据集通常很少 表型，尤其是针对行为和精神病表型。我们提出的 框架通过重新连接和重新评估稀有的挑战克服了这一挑战 变体载体及其家人，允许测量精神病学 表型远远超出了生物库中可用的表型。我们充分利用了 多学科团队，高级基因组技术，多样化的分析方法， 并详细介绍了大型大家庭样本的深层表型评估。我们 将使用大型高功率GWA和整个基因组测序数据集识别 在与物质相关的基因座中罕见的有害变体。之上 细胞系中稀有有害变体的功能验证，我们将使用一种新颖 将此类变体算入密歇根州基因组学倡议生物库的程序， 从而识别出稀有有害等位基因的载体。这些人，他们的 家庭将重新接触并接受对其的标准和量身定制的评估 药物使用/依赖史，精神病学，神经认知和社会心理 功能。拟议的框架提供了一种新方法来调查人类 GWAS的生物学命中率是识别治疗靶标的并改善我们的 了解成瘾的病因。