Genetic by Context Influence on Trajectories of Adolescent Health Risk Behaviors

描述(由申请人提供)：要了解青少年健康基因-环境相互作用在酒精使用、物质使用和攻击性行为危险行为的病因上的发展，需要检查遗传和环境变量及其相互作用。这项研究建议测试来自5个精选区域的遗传标记--5-羟色胺转运体基因(SLC6A4)、单胺氧化酶A基因(MAOA)、儿茶酚-O-甲基转移酶基因(COMT)、4型多巴胺受体基因(DRD4)，以及15号染色体上重叠三种尼古丁受体(CHRNA5-CHRNA3-CHRNB5)的高LD区域的一系列标签SNP与来自四个关键社会背景(家庭、同伴、学校和邻居)的基于理论的背景变量(压力、健康危险行为模式和社会控制)之间的相互作用和攻击性(总体上，以及对同龄人和日期)。目标1是确定这些遗传标记和健康危险行为的轨迹之间的关联是否受到假设方向上基于理论的上下文变量的调节。这项研究还旨在阐明哪些理论结构(目标2)和社会背景(目标3)在调节遗传标记与危险行为轨迹之间的关联方面最重要，以及哪些健康危险行为最受基因与环境相互作用的影响(目标4)。一项七波前瞻性队列研究(n=4000)已经提供了数据，用于测量11至19岁的健康危险行为和背景变量。在该研究中，使用了创新的测量技术，包括社会网络分析来测量同伴和学校背景，美国人口普查数据在区组水平(n=58)，以及青少年和父母自我报告来测量邻里背景。在这项拟议的研究中，将从现在的年轻人身上采集全血并进行基因分型。这些数据将与前瞻性研究的数据合并，以解决四个具体目标。这项研究的特点是从先前的研究中扩展了几个概念，包括评估交互作用对青少年健康危险行为的轨迹的影响，而不是对青少年健康危险行为的点估计，允许检查基因与环境的交互作用对青少年健康危险行为的影响如何在青春期改变，使用基于理论的背景调节因素，以及检查除主要研究的家庭背景之外的背景因素。拟议的研究还解决了候选基因-环境研究的显著方法学局限性，方法包括：对背景变量进行强有力的测量，选择数量有限的经验性合理的候选基因进行研究，采用前瞻性设计，采用K倍交叉验证程序，控制祖传遗传，即使在按性别分层时也有足够的能力检测适度。了解不可延展性基因之间的关联在何种条件下恶化或被中和，对于制定有效的公共卫生和个性化计划以促进青少年健康发展至关重要。公共卫生相关性：遗传背景对青少年健康危险行为轨迹的影响项目摘要-相关性吸烟、酗酒、非法药物使用和攻击性是重大的公共卫生问题。这项研究将有助于了解在何种情况下，不可延展的基因型与这些健康危险行为之间的关联被加剧或中和，这一理解对于制定有效的公共卫生和个性化计划以预防这些公共卫生问题和促进青少年健康发展至关重要。

DESCRIPTION (provided by applicant): Understanding the development of adolescent health gene-environment interactions on the etiology of alcohol use, substance use, and aggressive behavior risk behaviors requires examination of both genetic and environmental variables and their interactions. This study proposes to test interactions between genetic markers from five carefully selected regions - the serotonin transporter gene (SLC6A4), the monoamine oxidase A gene (MAOA), the catechol-O-methyltransferase gene (COMT), the type 4 dopamine receptor gene (DRD4), and a series of tag SNPs in a high LD region on chromosome 15 overlapping three nicotine receptors (CHRNA5-CHRNA3-CHRNB5) and theoretically-based contextual variables (stress, models of health risk behaviors, and social controls) from four key social contexts (family, peer, school, and neighborhood) on trajectories of adolescent tobacco use, alcohol misuse, illicit drug use, and aggression (in general and against peers and dates). Aim 1 is to determine if associations between these genetic markers and trajectories of health risk behaviors are moderated by theoretically-based contextual variables in the directions hypothesized. The study is intended also to illuminate which theoretical constructs (aim 2) and social contexts (aim 3) are most important in moderating associations between genetic markers and trajectories of risk behaviors, and which health risk behaviors are most influenced by gene-by-environment interactions (aim 4). Data are already available from a seven- wave prospective cohort study (n = 4000) for measuring the health risk behaviors and contextual variables from ages 11 through 19. In that study innovative measurement techniques were used including social network analyses to measure the peer and school context and U.S. Census data at the block group level (n = 58) and adolescent and parent self-reports to measure neighborhood context. For the proposed study, whole blood will be collected from the now young adults and genotyped. Those data will be merged with data from the prospective study to address the four specific aims. The study features several conceptual extensions from prior studies including assessing the influence of interactions on trajectories rather than point estimates of adolescent health risk behaviors, allowing for an examination of how the influence of gene-by-environment interactions on health risk behaviors change across adolescence, use of theoretically- based contextual moderators, and examination of moderators from contexts besides the predominately studied family context. The proposed study also addresses notable methodological limitations of candidate gene-by- environment studies by having strong measures of the contextual variables, selecting a limited number of empirically justified candidate genes to study, using a prospective design, incorporating a K-fold cross- validation procedure, controlling for ancestral heritage, and having sufficient power for detecting moderation, even when stratifying by gender. Understanding the conditions under which the associations between non- malleable genotypes are exacerbated or neutralized is crucial for developing effective public health and individualized programs to promote healthy adolescent development. PUBLIC HEALTH RELEVANCE: Genetic by Context Influence on Trajectories of Adolescent Health Risk Behaviors Project Summary - Relevance Tobacco use, alcohol misuse, illicit drug use, and aggression are significant public health problems. The study will contribute toward understanding the conditions under which the associations between non-malleable genotypes and these health risk behaviors are exacerbated or neutralized and this understanding is crucial for developing effective public health and individualized programs for preventing these public health problems and for promoting healthy adolescent development.