Investigating Methylation Patterns Associated with Alcohol Use and Addiction

描述（由申请人提供）：虽然生物识别基因研究长期以来一直表明饮酒行为和成瘾的实质性遗传性，但将这种影响映射到特定遗传变异上的进展缓慢，而且一旦发现，这些遗传变异只有适度的预测能力。DNA甲基化研究是对以序列变异为重点的遗传学研究的一个有希望的补充，因为甲基化与基因表达直接相关，可能被用作酒精障碍的生物标志物。本提案的总体目标是为候选人提供必要的培训和研究机会，以利用下一代测序方法，如甲基组测序，研究饮酒行为和成瘾，从而支持候选人成为该领域独立研究者的长期职业目标。一般培训目标包括加强对饮酒行为和成瘾以及统计遗传学的实质性问题的认识，并培养对生物信息学和计算机编程的熟练程度。这些领域拟议的培训包括课程作业、强化指导、暑期项目、阅读小组、系列研讨会和会议等环环相扣的项目，特别关注研究伦理方面的培训。直接指导是该计划的一个关键特点，可以接触到每个拟议培训领域的领先专家(例如，博士。埃德温·范登·奥德（Edwin van den Oord）和迈克尔·尼尔（Michael Neale）博士——统计遗传学、生物信息学和编程；迈克尔·迈尔斯（Michael Miles）博士和大卫·戈德曼（David Goldman）博士——饮酒行为和成瘾遗传学方面的实质性专业知识)代表了拟议训练计划的核心力量。候选人建议将获得的技能应用于项目的研究部分，通过进行多阶段的全甲基组分析来研究饮酒行为和成瘾。在方法上，该项目侧重于将基因组方法与统计模型相结合，以更好地了解疾病机制。这将通过汇集前所未有的全甲基组数据集来促进，包括来自瑞典国家人口登记处和EpiTwin项目样本的数据的荟合分析，总样本量约为5800人。在“发现”阶段的荟萃分析之后，将使用一种“黄金标准”技术，在大约500人的后续样本中验证最重要的发现，这种技术将精细地绘制与饮酒行为和成瘾相关的甲基化位点的位置。该项目将在最后的分析阶段得到进一步补充，在此阶段，因果模型将适用于验证的甲基化位点以及成瘾、健康和饮酒结果的数据，以调查甲基化位点与饮酒行为和成瘾之间的因果关系方向。一项啮齿动物研究将补充人类的工作，并将有助于在与饮酒行为和成瘾相关的甲基化位点是否可以用作酒精中毒的生物标志物这一问题上获得关注。

DESCRIPTION (provided by applicant): While biometric genetic studies have long indicated substantial heritability for drinking behaviors and addiction, progress in mapping this influence onto specific genetic variants has been slow and once found, these genetic variants have only modest predictive power. DNA methylation studies represent a promising complement to genetic studies focusing on sequence variation because methylation is directly related to gene expression and can potentially be used as a biomarker for alcohol disorders. The overarching goal of this proposal is to provide the candidate the training and research opportunities necessary to utilize next generation sequencing methods, such as methylome sequencing, to study drinking behaviors and addiction, thus supporting the candidate's long-term career goal of becoming an independent investigator in the area. General training goals include strengthening knowledge of substantive issues in drinking behaviors and addiction and statistical genetics, and building proficiency in bioinformatics and computer programming. Proposed training in these areas consists of an interlocking program of coursework, intensive mentoring, summer programs, reading groups, seminar series and conferences, with special attention to training in research ethics. Direct mentoring is a key feature of this program, with access to leading experts in each of the proposed training areas (i.e., Drs. Edwin van den Oord and Dr. Michael Neale - statistical genetics, bioinformatics and programming, Dr. Michael Miles and David Goldman - substantive expertise in the genetics of drinking behaviors and addiction) representing a core strength of the proposed training plan. The candidate proposes to apply acquired skills in the research portion of the project by conducting a multistage whole methylome analysis to study drinking behaviors and addiction. Methodologically, this project focuses on integrating genomic methods with statistical models to better understand disease mechanisms. This will be facilitated by bringing together an unprecedented combination of whole methylome datasets, including a meta-analysis of data from Swedish national population registries and the EpiTwin project sample, with a combined total sample size of approximately 5,800 individuals. The "discovery" phase meta-analysis will then be followed by validating the top findings in a follow-up sample of approximately 500 individuals using a "gold standard" technology that will fine map the locations of methylated sites associated with drinking behaviors and addiction. The project will be further complimented in a final analytical stage in which causal models will be fitted to data on validated methylation sites, and addiction, health and drinking outcomes to investigate the direction of causation between methylation sites and drinking behaviors and addiction. A rodent study will complement the human work and will help gain traction on the issue of whether methylation sites associated with drinking behaviors and addiction can be used as biomarkers for alcoholism.