Project 5 - Genetic architecture of alcohol use disorder using cross-trait genetic correlations and public next-generation sequencing studies

项目 5 - 使用跨性状遗传相关性和公共下一代测序研究的酒精使用障碍的遗传结构

• 批准号: 10633321
• 负责人: BRADLEY Todd WEBB
• 金额: $ 18.67万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633321
• 关键词: Address; Age; Alcohol abuse; Alcohol consumption; Alcohols; Alleles; Architecture; Catalogs; Child; Classification; Code; Communities; Complex; Data; Data Set; Detection; Disease; Elements; Epidemiology; Etiology; Family; First Births; Gene Frequency; Generations; Genes; Genetic; Genetic study; Genome; Genotype; Goals; Human; Individual; Intervention; Investigation; Large-Scale Sequencing; Measures; Medical; Mendelian randomization; Mental Health; Methods; Modeling; Molecular; Molecular Genetics; Nucleotides; Outcome; Pattern; Phenotype; Population; Prevention; Proteins; Risk; Risk Factors; Sample Size; Sampling; Source; Specificity; Testing; Time; Twin Multiple Birth; Untranslated Regions; Variant; Weight; addiction; alcohol behavior; alcohol use disorder; base; biobank; cigarette smoking; comorbidity; disorder risk; exome; exome sequencing; family genetics; functional genomics; gene network; genetic analysis; genetic architecture; genome sequencing; genome wide association study; genome-wide; improved; indexing; model building; next generation sequencing; novel; phenotypic data; physical conditioning; pleiotropism; population based; rare variant; risk variant; success; trait

Project Summary – Project 5 Recent advances in the study of human complex traits include 1) a growing catalog of robustly associated common variants found using genome-wide association studies (GWAS), 2) the ability to assess the contribution of rare variation through genome sequencing studies of both whole exomes (WES) and genomes (WGS), and 3) wide-spread cross-trait genetic correlation. For alcohol use disorder (AUD) and related phenotypes, there is an opportunity to discover novel rare variation and understand the overall pattern of evidence across the allele frequency spectrum including common and rare variation. One lesson from GWAS is that most robust associations do not create protein coding changes and some robust genome-wide significant variation does not reside in genes at all. As WES expands to include untranslated regions (UTRs) and WGS becomes affordable, there is a significant challenge in analyzing the variation that does not impact protein coding directly. Fortunately, there is a growing catalog of functional elements across the genome that can be interrogated to determine which harbor variants influencing AUD. For sequencing based analyses of rare variation, these functional elements showing enrichment can be leveraged to improve detection. As more variants associated with AUD are discovered and the catalog of traits with genetic correlations grows, determining how specific these variants are to AUD becomes more important. For example, do discovered loci influence a) addiction in general, b) alcohol consumption, or c) AUD specifically or do they non-specifically influence many physical or mental health outcomes. In addition to determining if loci, in aggregate or individually, can be considered primary or secondary AUD risk loci, understanding the direction of causation across traits and time is critically important to identifying opportunities for intervention. One powerful approach to investigate causative relationships is through Mendelian Randomization analysis. The overall goal of this project is to leverage existing twin, family, epidemiological, and molecular data in novel ways to a) discover loci harboring rare variants that influencing AUD without new molecular data generation, b) differentiate loci that influence common versus specific AUD liability factors, and c) understand the architecture of AUD using an integrated and iterative approach.

项目摘要 - 项目5 人类复杂性状研究的最新进展包括1）牢固相关的日益增长的目录 使用全基因组关联研究（GWAS）发现的常见变体，2）评估能力 通过基因组测序研究的罕见变异对整个外部（WES）和基因组的贡献 （WGS）和3）广泛的跨性状遗传相关性。用于饮酒障碍（AUD）及相关 表型，有机会发现新颖的稀有变化并了解 跨等位基因频谱的证据，包括常见和罕见变化。 GWAS的一堂课 是，大多数强大的关联不会产生蛋白质编码的变化和一些稳健的基因组的变化 基因根本不存在显着变化。随着WES的扩展，包括未翻译区域（UTRS） WGS变得负担得起，分析不影响的变化存在重大挑战 蛋白质编码直接。幸运的是，整个基因组的功能元素目录越来越多， 可以审问以确定哪些港口变体会影响AUD。用于基于测序的分析 极少数变化，这些表现出富集的功能元件可以利用以改善检测。更多 发现了与AUD相关的变体，并且具有遗传相关性的特征目录会增长， 确定这些变体对AUD的具体程度变得更加重要。例如，确实发现了基因座 影响a）总体上成瘾，b）饮酒，或c）专门的AUD或它们是非特殊的 影响许多身体或心理健康结果。除了确定是否本地化外，总计还是 单独认为可以被视为主要或次级AUD风险基因座，了解病毒的方向 跨性格和时间对于确定干预机会至关重要。一种强大的方法 研究计算关系是通过门德尔随机分析。总体目标 项目是利用现有的双胞胎，家庭，流行病学和分子数据，以新颖的方式a）发现基因座 具有影响AUD的稀有变体，而无需新的分子数据生成，b）区分基因座 影响常见的和特定的AUD责任因素，c）使用一个AUD的体系结构 集成和迭代的方法。