Genetic and environmental contributions to drinking milestones in youth

描述（由申请人提供）：开始于青年时期的酒精使用行为是成年期酒精使用障碍的重要因素。对成年人的大规模研究已经确定了在全基因组水平上与物质使用障碍相关的特定遗传变异。这些遗传变异个体和其他风险因素对早期饮酒行为的影响程度尚不完全清楚。该项目的目标是 确定在成年人中发现的遗传变异是否影响青年饮酒里程碑的发展，以及重要的环境风险因素如何改变这些影响。我们将使用现有的纵向样本的欧洲和非洲裔美国青年收集通过合作研究酒精中毒的遗传学（COGA）。我们的中心假设是遗传变异会影响早期酒精相关问题，环境因素会改变这种影响。根据申请人进行的分析生成的强有力的初步数据，将在两个特定目标中对该假设进行检查。目的1将测试从饮酒开始到DSM-5酒精使用障碍的青少年饮酒行为中已建立的靶向遗传变异的影响。我们将首先研究乙醇脱氢酶（ADH）的功能变体，这些变体已被证明对成人酒精使用障碍具有全基因组的显著影响。然后，我们将研究CHRNA 5-CHRNA 3-CHRNAB 4烟碱受体亚基基因的变异，这对吸烟行为具有全基因组意义，越来越多的证据表明与成人酒精依赖有关。目标2将测试已知的早期饮酒行为的环境风险因素如何改变这些靶向遗传变异的影响。我们将重点放在同伴饮酒和父母的监督，这两个环境以前已被证明会影响青少年饮酒模式。这项研究意义重大，因为它有望为早期饮酒行为的复杂病因学提供见解。更好地了解特定的遗传和环境因素如何促成这些早期行为，将增加我们对导致酒精使用障碍的发育过程的基本知识。最终，确定影响潜在遗传脆弱性的可改变的风险因素有可能为新的干预措施提供信息，以减轻这种严重疾病的负担。

DESCRIPTION (provided by applicant): Alcohol use behaviors that begin in youth are important contributors to alcohol use disorders in adulthood. Large-scale studies of adults have identified specific genetic variants that are associated at a genome-wide level with substance use disorders. The extent to which these genetic variants, individually and with other risk factors, influence early drinking behaviors is not fully understood. The goal of this project is to determine whether genetic variants identified in adults impact the development of drinking milestones in youth and how important environmental risk factors modify these effects. We will use an existing longitudinal sample of European and African American youth collected through the Collaborative Study on the Genetics of Alcoholism (COGA). Our central hypothesis is that genetic variants will affect early alcohol- related problems and that environmental factors will modify this effect. Guided by strong preliminary data generated from analyses performed by the applicant, this hypothesis will be examined in two specific aims. Aim 1 will test the effect of wel-established targeted genetic variants on adolescent drinking behaviors from drinking initiation to DSM-5 alcohol use disorders. We will initially examine functional variants in the enzyme alcohol dehydrogenase (ADH) that have been shown to have a genome-wide significant effect on alcohol use disorders in adults. We will then examine variation in the CHRNA5-CHRNA3-CHRNAB4 nicotinic receptor subunit genes that is genome-wide significant for smoking behaviors, with growing evidence for an association with adult alcohol dependence. Aim 2 will then test how known environmental risk factors for early drinking behaviors modify the effect of these targeted genetic variants. We will focus on the two environments of peer drinking and parental monitoring, which have previously been shown to influence youth drinking patterns. The proposed research is significant because it is expected to provide insight into the complex etiology of early drinking behaviors. A better understanding of how specific genetic and environmental factors contribute to these early behaviors will add to our fundamental knowledge of the developmental processes that lead to alcohol use disorders. Ultimately, identification of modifiable risk factors that influence underlying genetic vulnerabilities has the potential to infom new interventions to reduce the burden of this severe disease.