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）越来越多的与人类复杂性状密切相关的 使用全基因组关联研究（GWAS）发现的常见变异，2）评估 通过全外显子组（WES）和基因组的基因组测序研究来贡献罕见变异 (WGS)（3）广泛的交叉性状遗传相关。酒精使用障碍（AUD）及相关 表型，有机会发现新的罕见变异，并了解整体模式， 等位基因频率谱的证据，包括常见和罕见的变异。GWAS的一个教训 大多数强关联不会产生蛋白质编码变化， 显著的变异根本不存在于基因中。随着WES扩展到包括非翻译区（UTR） WGS变得负担得起，在分析不影响的变化方面存在重大挑战 直接编码蛋白质。幸运的是，基因组中的功能元件目录越来越多， 可以询问以确定哪些港口变体影响AUD。对于基于测序的 罕见的变异，这些显示富集的功能元件可用于改善检测。随着更多 与AUD相关的变异被发现，具有遗传相关性的性状目录也在增长， 确定这些变体对AUD的特异性变得更加重要。例如，发现的基因座 影响a）一般成瘾，B）酒精消费，或c）特定AUD或非特定AUD 影响许多身体或心理健康的结果。除了确定基因座，总体上或 单独地，可以被认为是主要或次要AUD风险位点，了解因果关系的方向 跨特征和时间的研究对于确定干预机会至关重要。一个强大的方法 研究因果关系是通过孟德尔随机化分析。这个项目的总体目标是 该项目是利用现有的双胞胎，家庭，流行病学和分子数据的新方法，以a）发现基因座 携带影响AUD的罕见变体而不产生新的分子数据，B）区分 影响共同与特定澳元负债因素，以及c）使用 综合和迭代方法。