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

描绘基因、环境、

基本信息

批准号：
8712447
负责人：
BRIAN M HICKS
金额：
$ 22.71万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8712447
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 rare variant risk variant success trait trend young adult

项目摘要

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）：该提案的目的是验证用于物质使用障碍（SUDS）的基因，环境和发育（GED）相互作用的模型。关于SUD的发育过程和环境风险已经知道很多，基因组广泛关联研究（GWAS）的最新进展具有识别SUD的新风险基因的希望。然而，很少有研究将这些因素中的每一个都纳入了程序化研究线。这需要多次对与SUD相关的表型和环境危险因素（例如，家庭，同龄人，学校/工作，工作，压力大的生活事件）进行基因分型和评估的前瞻性队列样本。对这种类型的新研究具有足够的能力来检测单个基因的小效果，并且与环境的相互作用将非常昂贵且耗时。但是，我们认为，现在可以通过利用具有GWAS基因分型的现有前瞻性队列研究来获得这些知识。我们提出了一种研究SUD的GED相互作用的策略。 SUD是出色的复杂表型，可以检查GED相互作用，因为它们是常见的，可遗传的，并且与多种环境风险因素有关。 SUD也是检查开发的理想选择，因为它们在谨慎的启动事件之前就无法出现，从而提供了警戒前风险阶段与主动风险阶段之间的明确分界。最后，有几个现有样本在暴露于环境风险和SUD从启动之前到严重和持续存在的问题的进展方面的特征很好。我们将使用明尼苏达州双胞胎和家庭研究中心（MCTFR； n = 8405）的前瞻性双胞胎和采用研究进行一系列分析，并在7项纵向研究中进行了复制分析（合并n = 7795；高风险和基于人口的采样设计），以测试和验证GEDPLAY模型的模型。由于GED相互作用研究的初始阶段将需要赢得潜在的因果因素，目标1是开发多基因风险评分，以汇总多种遗传标记的影响，以提高检测遗传作用的能力。目的2是使用纵向混合模型对与SUD相关表型的发展轨迹进行建模，其中使用年龄和环境变量来解释SUD的个体差异。然后将多基因风险评分添加到模型中，以说明年龄（G-d）和环境（G-E）变量对SUD的影响的变化。 AIM 3是为了荟萃分析的目的复制GED发现，因为这为检测效果和最可靠的效果大小估计提供了最大的能力。 AIM 4是扩展我们的GED模型，以包括其他基因组数据（外显子和测序）。这些数据集和我们的方法的丰富性提供了一种特别有效的方法，可以加速我们对泡沫基础的因果过程的理解，我们希望该项目跨站点的合作将导致持续的合作，以进一步加速发现的步伐。