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）：该提案的目标是验证物质使用障碍 (SUD) 的基因、环境和发育 (GED) 相互作用模型。人们对 SUD 的发育过程和环境风险已经了解很多，而全基因组关联研究 (GWAS) 的最新进展有望识别出 SUD 的新风险基因。然而，很少有研究将这些因素整合到一个有计划的研究中。这需要对前瞻性队列样本进行基因分型，并多次评估 SUD 相关表型和环境风险因素（例如家庭、同伴、学校/工作、压力生活事件）。进行此类具有足够能力的新研究来检测个体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，我们认为现在可以通过利用现有的 GWAS 基因分型前瞻性队列研究来获得大部分知识。 我们提出这样一个策略来研究 SUD 的 GED 相互作用。 SUD 是检查 GED 相互作用的绝佳复杂表型，因为它们很常见、可遗传，并且与多种环境风险因素相关。 SUD 也是检查发育的理想选择，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活跃风险阶段之间提供明确的界限。最后，有几个现有样本在暴露于环境风险和 SUD 从开始使用之前到严重和持续问题使用的进展方面得到了很好的表征。 我们将使用明尼苏达双胞胎和家庭研究中心 (MCTFR; n=8405) 的前瞻性双胞胎和收养研究进行一系列分析，并在 7 项纵向研究中进行复制分析（合并 n=7795；高风险和基于人群的研究）抽样设计）来测试和验证 GED 相互作用模型。由于 GED 相互作用研究的初始阶段需要筛选潜在的致病因素，目标 1 是开发多遗传风险评分，汇总多个遗传标记的影响，以提高检测遗传影响的能力。目标 2 是使用纵向混合模型对 SUD 相关表型的发育轨迹进行建模，其中年龄和环境变量用于解释 SUD 的个体差异。然后将多遗传风险评分添加到模型中，以解释年龄 (G-D) 和环境 (G-E) 变量对 SUD 影响的变化。目标 3 是使用其他样本复制 GED 结果以进行荟萃分析，因为这提供了检测效果的最大能力以及对效果大小最可靠的估计。目标 4 是扩展我们的 GED 模型，以包含可用的其他基因组数据（外显子组和测序）。这些数据集的丰富性和我们的方法提供了一种特别具有成本效益的方式来加速我们对 SUD 背后因果过程的理解，我们希望该项目的跨站点合作将导致持续的合作，从而进一步加快发现的步伐。