Genetic by Context Influence on Trajectories of Adolescent Health Risk Behaviors

描述（由申请人提供）：了解青少年健康基因-环境相互作用对酒精使用，物质使用和攻击性行为风险行为的病因学的发展需要检查遗传和环境变量及其相互作用。这项研究提出测试来自五个精心选择的区域的遗传标记之间的相互作用--5-羟色胺转运体基因（SLC 6A 4）、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（DRD 4）、以及在15号染色体上与三个尼古丁受体重叠的高LD区域中的一系列标签SNP（CHRNA 5-CHRNA 3-CHRNB 5）和基于理论的上下文变量（压力，健康风险行为模型和社会控制）从四个关键的社会背景（家庭，同伴，学校和邻里）对青少年烟草使用的轨迹，酒精滥用，非法药物使用，和侵略（一般和对同龄人和日期）。目的1是确定这些遗传标记和健康风险行为轨迹之间的关联是否受到假设方向上基于理论的背景变量的调节。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）在调节遗传标记和风险行为轨迹之间的关联方面最重要，哪些健康风险行为最受基因与环境相互作用的影响（目标4）。数据已经从一个七波前瞻性队列研究（n = 4000）中获得，用于测量11岁至19岁的健康风险行为和背景变量。在这项研究中，创新的测量技术，包括社会网络分析，以衡量同龄人和学校的背景和美国人口普查数据在块组水平（n = 58）和青少年和家长的自我报告，以衡量邻里的情况。对于拟定的研究，将从现在的年轻成年人中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以前的研究中扩展了几个概念，包括评估相互作用对轨迹的影响，而不是对青少年健康风险行为的点估计，允许检查基因与环境相互作用对青少年健康风险行为的影响如何变化，使用基于理论的背景调节剂，以及除了主要研究的家庭背景外，还检查背景调节剂。拟议的研究还解决了显着的方法局限性的候选基因环境研究的背景变量的强有力的措施，选择了有限数量的经验证明候选基因进行研究，使用前瞻性设计，纳入K倍交叉验证程序，控制祖先的遗产，并有足够的权力检测适度，即使按性别分层。了解非可塑性基因型之间的关联是在何种条件下加剧或中和的，对于制定有效的公共卫生和个性化计划以促进健康的青少年发展至关重要。公共卫生相关性：青少年健康风险行为轨迹的遗传背景影响项目摘要-相关性烟草使用，酒精滥用，非法药物使用和侵略是重要的公共卫生问题。该研究将有助于了解非可塑性基因型与这些健康风险行为之间的关联加剧或中和的条件，这种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健康的青少年发展至关重要。

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.