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.

项目总结/文摘