Delineating Gene, Environment, & Development Interplay in Substance Use Disorders

描绘基因、环境、

• 批准号: 8576161
• 负责人: BRIAN M HICKS
• 金额: $ 25.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576161
• 关键词: Accounting; Achievement; Adoption; Age; Age of Onset; Alcohol or Other Drugs use; Alcohols; Biological; Child; Childhood; Code; Cohort Studies; Collaborations; Complex; Data; Data Analyses; Data Set; Dependence; Derivation procedure; Development; Disease; Environment; Environmental Risk Factor; Etiology; Event; Exhibits; Exposure to; Family; Family Research; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Home environment; Individual; Individual Differences; Investigation; Knowledge; Lead; Left; Life; Link; Literature; Longitudinal Studies; Marriage; Measures; Meta-Analysis; Methods; Minnesota; Modeling; Nicotine; Parents; Pattern; Phenotype; Process; Public Health; Research; Research Design; Research Personnel; Risk; Risk Factors; Sampling; Schools; Series; Site; Staging; Substance Use Disorder; Symptoms; Testing; Time; Twin Multiple Birth; Variant; Work; age effect; base; cohort; cost effective; cost efficient; design; exome; exome sequencing; flexibility; gene interaction; genome sequencing; genome wide association study; genome-wide; genotyping technology; high risk; improved; insight; novel; offspring; peer; population based; programs; prospective; public health relevance; success; trait; trend; young adult

DESCRIPTION (provided by applicant): The goal of this proposal is to validate models of gene, environment, and developmental (GED) interplay for substance use disorders (SUDs). Much is already known about the developmental course and environmental risk for SUDs, and recent advances in genome wide association studies (GWAS) hold the promise for identifying novel risk genes for SUDs. Few studies, however, have integrated each of these factors into a programmatic line of research. This requires prospective cohort samples that have been genotyped and assessed on multiple occasions for SUD-related phenotypes and environmental risk factors (e.g., family, peers, school/work, stressful life events). Conducting new studies of this type with sufficient power to detect the small effects for individual genes and interactions with the environment will be extremely expensive and time consuming. We posit, however, that much of this knowledge can be obtained now by leveraging existing prospective cohort studies that have GWAS genotyping. We propose such a strategy to investigate GED interplay for SUDs. SUDs are excellent complex phenotypes to examine GED interplay, as they are common, heritable, and are associated with several environmental risk factors. SUDs are also ideal for examining development, as they cannot emerge prior to the discreet event of initiation, providing for a clear demarcation between a pre-morbid risk stage and an active risk stage. Finally, there are several existing samples that have been well characterized in terms of exposure to environmental risk and progression of SUDs from prior to initiation to severe and persistent problem use. We will conduct a series of analyses using the prospective twin and adoption studies of the Minnesota Center for Twin and Family Research (MCTFR; n=8405) and replication analyses in 7 longitudinal studies (combined n=7795; high-risk and population-based sampling design) to test and validate models of GED interplay. As the initial stage of GED interplay research will require winnowing down potential causal factors, Aim 1 is to develop polygenetic risk scores that aggregate the effects of multiple genetic markers to improve power to detect genetic effects. Aim 2 is to model the developmental trajectories of SUD-related phenotypes using longitudinal mixed models, wherein age and environmental variables are used to account for individual differences in SUDs. Polygenetic risk scores are then added to the model to account for variation in the effects for age (G-D) and environmental (G-E) variables on SUDs. Aim 3 is to replicate GED findings using the other samples for the purpose of meta-analyses, as this provides the greatest power to detect effects and the most reliable estimates of effect size. Aim 4 is to expand our GED models to include other genomic data (exome and sequencing) as it becomes available. The richness of these data sets and our approach provides an especially cost efficient way to accelerate our understanding of the causal processes underlying SUDs, and we hope that cooperation across sites on this project will lead to continued collaborations that will further accelerate the pace of discovery.

描述(由申请人提供)：本提案的目标是验证物质使用障碍(SODS)的基因、环境和发育(GED)相互作用的模型。关于肥胖症的发育过程和环境风险已经有了很多的了解，最近全基因组关联研究的进展为识别新的肥胖症风险基因提供了希望。然而，很少有研究将这些因素中的每一个都整合到一系列研究中。这需要经过多次基因分型和评估的预期队列样本，以确定与SUD相关的表型和环境风险因素(例如，家庭、同龄人、学校/工作、应激性生活事件)。以足够的能力进行这种类型的新研究，以检测单个基因的微小影响以及与环境的相互作用，将是极其昂贵和耗时的。然而，我们假设，这些知识中的大部分现在可以通过利用现有的前瞻性队列研究获得，这些研究已经进行了GWAS型基因分型。我们提出了这样一种策略来研究GED与SUDS的相互作用。SOD是检测GED相互作用的极好的复杂表型，因为它们是常见的、可遗传的，并与几个环境风险因素有关。SOD也是检查发育的理想方法，因为它们不能在谨慎的启动事件之前出现，从而在发病前风险阶段和积极风险阶段之间提供了明确的分界。最后，有几个现有的样本在暴露于环境风险以及肥皂泡从开始使用到严重和持续问题使用的进展方面已经有了很好的特征。我们将使用明尼苏达双胞胎和家庭研究中心(MCTFR；n=8405)的预期双胞胎和收养研究以及7项纵向研究(合并n=7795；高风险和基于人群的抽样设计)的重复分析进行一系列分析，以测试和验证GED相互作用的模型。由于GED相互作用研究的初始阶段将需要筛选潜在的因果因素，目标1是开发聚合多个遗传标记的影响的多基因风险评分，以提高检测遗传效应的能力。目标2是使用纵向混合模型模拟与SUD相关的表型的发育轨迹，其中年龄和环境变量被用来解释SUD的个体差异。然后将多基因风险分数添加到模型中，以考虑年龄(G-D)和环境(G-E)变量对SODS的影响的变化。目标3是为了荟萃分析的目的，使用其他样本复制GED的结果，因为这提供了检测效应的最大能力和对效应大小的最可靠估计。目标4是扩展我们的GED模型，以便在获得其他基因组数据(外显子组和测序)时将其包括在内。这些丰富的数据集和我们的方法提供了一种特别经济高效的方式来加快我们对SOD背后的因果过程的理解，我们希望这个项目上的跨站点合作将导致继续合作，从而进一步加快发现的步伐。