Rare Sequence Variation and DNA Methylation: Effects on Alcohol and Tobacco Use Phenotypes

7.项目摘要/摘要 长期目标 这个项目的主要目标是：(1)评估蛋白质编码中罕见和常见变异的影响 和非编码基因区，以及烟酒使用表型的调控基因间隔区； 在当前酒精和烟草使用的背景下测试差异DNA甲基化；以及(3)调查 调控序列变异与DNA甲基化的关系及其联合作用 酒精和烟草的使用和依赖。鉴于酒精和酒精的共同遗传病因学 烟草使用，长期的职业目标是制定一项研究计划，为预防和 通过描述导致这些特征的病理生理过程来制定治疗策略。 具体目标 这项提议的主要研究目的有两个。第一个目标是研究蛋白质编码区和 非编码DNA，以测试不同的优先排序和分组方法通知基因的能力 酒精和烟草使用和依赖的协会研究。确定优先级的方法将包括使用 生物信息学工具，用于选择和分配权重，以确定基因和基因内可能导致的罕见和常见变异 易受DNA甲基化影响的区域。这些权重将被合并到基于集合的分析中， 结合罕见和常见的变异来测试与酒精和烟草使用表型的关联。这个 第二个目标是评估这些优先级排序和基于集合的分析方法为分析提供信息的能力 DNA甲基化微阵列数据。具体地说，这一目标的重点是测试表观遗传调节 遗传风险，以确定该区域的DNA序列变异与 甲基化在预测烟酒使用和依赖中的作用。分析将使用以下工具进行 酒精依赖家族性研究中的全基因组测序和DNA甲基化数据 敏感度。在获奖期间，培训将通过(1)课程作业，(2)参加 教学研讨会，以及(3)与高级统计遗传学和DNA方面的专家顾问的会议 甲基化方法和分析。 意义 该项目的结果将为酒精的病因和发展的分子遗传学研究提供信息 烟草的使用和依赖。全基因组序列和表观遗传学数据的可用性不断提高 对复杂特征的研究提出了计算和理论上的挑战，特别是在解释方面 这些区域中罕见和常见的非编码变异和表观遗传过程的广泛程度。因此， 这个项目的结果将推动信息学方法来研究这些特征和我们的理解 生物因素对物质使用障碍风险的贡献。

7. Project Summary/Abstract Long-Term Objectives The broad goals of this project are to (1) evaluate the effects of rare and common variation in protein-coding and non-coding gene regions, and regulatory intergenic regions on alcohol and tobacco use phenotypes; (2) test for differential DNA methylation in the context of current alcohol and tobacco use; and (3) investigate the relationship between regulatory sequence variation and DNA methylation and their combined effects on alcohol and tobacco use and dependence. Given the substantial shared genetic etiology for alcohol and tobacco use, the long-term career objective is to develop a program of research that informs prevention and treatment strategies by characterizing the pathophysiological processes that contribute to these traits. Specific Aims There are two primary research aims of this proposal. The first aim focuses on regions of protein-coding and non-coding DNA in order to test the ability of different prioritization and grouping methods to inform genetic association studies of alcohol and tobacco use and dependence. Prioritization methods will include the use of bioinformatics tools to select and assign weights to likely causal rare and common variants within genes and regions susceptible to DNA methylation. These weights will be incorporated into set-based analyses that combine rare and common variants to test for association with alcohol and tobacco use phenotypes. The second aim will evaluate the ability of these prioritization and set-based analytic methods to inform the analysis of DNA methylation microarray data. Specifically, the focus of this aim is to test for epigenetic mediation of genetic risk to determine the extent to which DNA sequence variants in the region are related to level of methylation in the prediction of alcohol and tobacco use and dependence. Analyses will be conducted using whole-genome sequencing and DNA methylation data from a family-based study of alcohol dependence susceptibility. During the period of the award, training will be obtained via (1) coursework, (2) attendance at didactic workshops, and (3) meetings with expert consultants in advanced statistical genetics and DNA methylation methods and analysis. Significance Results from this project will inform molecular genetic studies on the etiology and development of alcohol and tobacco use and dependence. The increasing availability of whole-genome sequence and epigenetic data poses a computational and theoretical challenge for research on complex traits, particularly in the interpretation of the vast extent of rare and common non-coding variation and epigenetic processes in these regions. Thus, results from this project will advance informatics approaches to the study of such traits and our understanding of biological contributions to the risk for substance use disorders.