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

项目总结/摘要 描述：参见说明。这必须包含一个适合向公众传播的拟议活动的摘要（没有 专有/机密信息）。它应该是一个独立的项目描述，并包含一个目标和方法的声明， 就业。它应该对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。 拟议研究的目标是发现生物学上重要的遗传变异， 海洛因成瘾我们将利用现有数据绘制生物学途径和遗传变异的影响，例如 对人脑中基因调控（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进行基于通路的全基因组关联研究， 功能加权GWAS分析海洛因成瘾使用最大的样本量，到目前为止， 表型（发现总N= 52，362，独立复制总N= 24，205）。 成瘾的慢性、缓解/复发性脑部疾病影响着数百万美国公民，花费数十亿美元。 美元每年。海洛因成瘾的流行及其对公共卫生的影响日益严重（例如， 连续14年增加过量死亡人数）。海洛因成瘾的遗传性很大（约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， 和候选基因研究中，很少有特定的遗传变异被最终确定为这种疾病。 成功的GWAS和其他复杂疾病的基因图谱研究强调了三个关键因素： (1)绝大多数可重复相关的遗传变异是功能性的，或者是编码变异， 组织特异性;（3）样本量通常需要10，000。 编码蛋白质的变化或非编码变异，可能发挥调控作用;（2）基因调控是高度 我们的建议利用了这些事实， 一种新的方法，以基因发现成瘾跨越三个目标。 ·具体目标1：对海洛因成瘾（N= 52，362）进行基于路径的GWAS分析，并测试 独立重复（N= 24，205）。 ·具体目标2：整合关于人脑中假定变异功能的现有和新信息 并优化fwGWAS方法。 ·具体目标3：对海洛因成瘾进行功能加权GWAS分析， 独立复制。 我们基于路径的GWAS和功能加权的GWAS方法将大大提高 通过基于已知基因通路的知情分析，在标准GWAS上有意义的发现， 遗传变异的生物相关性，特别是在大脑中，同时保留了基因组范围。逻辑 我们的方法是直接的，但创新，闪耀着生物学相关的变异， 发现海洛因成瘾的新基因区域

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.