Harnessing Knowledge of Gene Function in Brain Tissue for Discovering Biology Underlying Heroin Addiction

利用脑组织基因功能知识来发现海洛因成瘾背后的生物学

• 批准号: 10116351
• 负责人: Eric Otto Johnson
• 金额: $ 77.5万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116351
• 关键词: Affect; African American; Alzheimer' s Disease; American; Beds; Biological; Biological Process; Biology; Blood; Brain; Brain Diseases; Candidate Disease Gene; Cannabis; Chromosome Mapping; Chronic; Code; Complex; Confidential Information; DNA Methylation; Data; Data Set; Databases; Disease; Drug abuse; European; Gene Expression Regulation; Genes; Genetic; Genome; Genotype; Goals; Heritability; Heroin; Heroin Dependence; Human; Illicit Drugs; Instruction; Knowledge; Light; Logic; Maps; Meta-Analysis; Methods; Methylation; National Institute of Drug Abuse; Opiate Addiction; Opioid; Opioid Receptor; Parkinson Disease; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Population Control; Prevalence; Proteins; Public Health; Quantitative Trait Loci; Receptor Gene; Relapse; Research; Resources; Risk; Route; Running; Sample Size; Sampling; Schizophrenia; Substance Use Disorder; Testing; Tissues; Untranslated RNA; Variant; Weight; addiction; analytical method; base; brain tissue; cost; database of Genotypes and Phenotypes; gene discovery; gene function; genetic variant; genome wide association study; genome-wide; genome-wide analysis; heroin use; improved; innovation; mRNA Expression; novel strategies; overdose death; prescription opioid abuse; protein function; psychogenetics; societal costs

PROJECT SUMMARY/ABSTRACT DESCRIPTION: See instructions. This must contain a summary of the proposed activity suitable for dissemination to the public (no proprietary/confidential information). It should be a self-contained description of the project and contain a statement of objectives and methods to be employed. It should be informative to other persons working in the same or related fields. DO NOT EXCEED THE SPACE PROVIDED. The goal of the proposed research is to discover biologically important genetic variants underlying risk for heroin addiction. We will use existing data to map biological pathways and genetic variants' effects, such as effects on gene regulation (DNA methylation and mRNA expression) and protein function in human brain tissue. We will apply this knowledge to conduct pathway-based genome-wide association study and the first function-weighted GWAS analyses of heroin addiction using the largest sample size, by far, for this phenotype to date (total N=52,362 for discovery and N=24,205 for independent replication). The chronic, remitting/relapsing brain disease of addiction affects millions of US citizens and costs billions of dollars per year. The prevalence of heroin addiction and its public health consequences are growing (e.g., increasing overdose deaths for 14 years running). Heritability of heroin addiction is substantial (~60%). However, after more than 30 years of research, including four standard GWAS analyses and many linkage and candidate gene studies, few specific genetic variants have been conclusively identified for this disease. Successful GWAS and other gene-mapping studies for complex diseases highlight three critical factors: (1) the vast majority of reproducibly associated genetic variants are functional, either coding variants that tissue specific; and (3) sample sizes ≫10,000 are often necessary. encode protein changes or noncoding variants that may exert regulatory effects; (2) gene regulation is highly Our proposal capitalizes on these facts in a novel approach to gene discovery for addiction across three aims. • Specific Aim 1: Conduct pathway-based GWAS analyses of heroin addiction (N=52,362) and test for independent replication (N=24,205). • Specific Aim 2: Integrate available and new information on putative variant function in human brain and optimize fwGWAS methods. • Specific Aim 3: Conduct function-weighted GWAS analyses of heroin addiction and test for independent replication. Our pathway-based GWAS and function-weighted GWAS approaches will greatly improve the likelihood of meaningful discovery over standard GWAS through informed analyses based on known gene pathways and genetic variants' biological relevance specifically in the brain, while retaining a genome-wide scope. The logic of our approach is straightforward yet innovative, shining the brightest light on biologically relevant variants to uncover new gene regions underlying heroin addiction.

项目摘要/摘要 说明：请参阅说明。它必须包含适合向公众传播的拟议活动的摘要(否 专有/机密信息)。它应该是对项目的独立描述，并包含对目标和方法的声明 受雇的。它应该为在相同或相关领域工作的其他人提供信息。不要超过所提供的空间。 这项拟议的研究的目标是发现潜在的具有生物学意义的遗传变异。 海洛因成瘾。我们将使用现有的数据来绘制生物路径和遗传变异的影响图，例如 对人脑基因调控(DNA甲基化和mRNA表达)和蛋白质功能的影响 组织。我们将应用这些知识来进行基于路径的全基因组关联研究，并将第一个 迄今为止，使用最大样本量对海洛因成瘾进行了功能加权的GWAS分析 到目前为止的表型(发现的总N=52,362，独立复制的N=24,205)。 这种慢性、缓解性/复发性的大脑疾病成瘾影响着数百万美国公民，并造成数十亿美元的损失 一年一美元。海洛因成瘾的流行率及其对公共健康的影响正在增长(例如， 服药过量死亡人数连续14年增加)。海洛因成瘾的遗传力很大(~60%)。 然而，经过30多年的研究，包括四个标准的GWAS分析和许多联系 和候选基因研究，很少有特定的遗传变异被最终确定为这种疾病。 针对复杂疾病的成功的全球基因图谱和其他基因图谱研究突出了三个关键因素： (1)绝大多数可重复相关的遗传变异都是功能性的，要么编码变异，要么 组织特异性；以及(3)样本大小≫10,000通常是必要的。 编码可能发挥调控作用的蛋白质变化或非编码变体；(2)基因高度调控 我们的建议充分利用了这些事实 一种新的跨越三个目标的成瘾基因发现方法。 ·具体目标1：对海洛因成瘾进行基于途径的全球海洛因成瘾分析(N=52,362)，并测试 独立复制(N=24,205)。 ·具体目标2：整合关于人脑假定变异功能的现有信息和新信息 并对fwGwas方法进行了优化。 ·具体目标3：对海洛因成瘾进行按职能加权的全球海洛因成瘾分析，并测试 独立复制。 我们基于路径的GWA和功能加权GWA方法将极大地提高 通过基于已知基因途径和信息分析的知情分析，在标准GWAS上有意义的发现 基因变异的生物学相关性，特别是在大脑中，同时保持全基因组范围。其中的逻辑 我们的方法是直截了当的，但也是创新的，将最明亮的光照射到与生物相关的变体上 发现海洛因成瘾的新基因区域。

项目成果

Evaluating 17 methods incorporating biological function with GWAS summary statistics to accelerate discovery demonstrates a tradeoff between high sensitivity and high positive predictive value.

• DOI: 10.1038/s42003-023-05413-w
• 发表时间: 2023-11-24
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Moore, Amy;Marks, Jesse A.;Quach, Bryan C.;Guo, Yuelong;Bierut, Laura J.;Gaddis, Nathan C.;Hancock, Dana B.;Page, Grier P.;Johnson, Eric O.
• 通讯作者: Johnson, Eric O.