Testing Gene-Testosterone Interplay in Adolescent Alcohol Use

测试青少年饮酒中基因-睾酮相互作用

• 批准号: 8764887
• 负责人: Kathryn Paige Harden
• 金额: $ 31.19万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764887
• 关键词: Accounting; Address; Adolescence; Adolescent; Affect; Age; Alcohol consumption; Alcohol or Other Drugs use; Behavior; Behavioral; Behavioral Genetics; Brain; Childhood; Chronic; Circadian Rhythms; Complex; Data; Development; Disease; Endocrine; Endocrinology; Epigenetic Process; Exploratory/Developmental Grant; Female; Future; Gene Expression; Genes; Genetic; Genetic Models; Genetic Research; Genetic Risk; Genetic Transcription; Genome; Genomics; Gonadal Steroid Hormones; Hair; Hormonal; Hormonal Change; Hormones; Human; Individual; Individual Differences; Link; Male Adolescents; Measurement; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Neuraxis; Neurosciences; Noise; Parents; Participant; Pathway interactions; Patient Self-Report; Phenotype; Plague; Protocols documentation; Quantitative Genetics; Records; Reporting; Research; Resources; Rewards; Risk; Risk-Taking; Saliva; Salivary; Sampling; Schools; Sex Characteristics; Signal Transduction; Stream; Structure; Surveys; Technology; Testing; Testosterone; Twin Multiple Birth; Variant; Youth; base; boys; critical period; density; early onset; endophenotype; genetic analysis; genetic association; girls; high reward; high risk; male; new technology; novel; psychobiology; public health relevance; relating to nervous system; response; sex; underage drinking

DESCRIPTION (provided by applicant): Adolescence is a critical period for the initiation and escalation of alcohol use and for the emergence of sex differences in alcohol use. The proposed research will test how changes in testosterone (T) during adolescence intersect with genetic influences on the development of alcohol use and related risk-taking behaviors. T levels increase dramatically from childhood through adolescence, particularly in males. Adolescent increases in T affect brain structure and function, including neural response to reward. Moreover, behavioral studies have found that individual differences in T predict alcohol use phenotypes, with stronger associations seen in boys than in girls. A largely independent stream of behavioral genetic research has established that genetic influences on substance use and related risk-taking behaviors increase over the course of adolescence. How these genetic influences intersect with hormonal changes during adolescence is unknown, as endocrine measures and behavioral genetic data have rarely been integrated. This gap is partly due to methodological challenges associated with measuring hormones in saliva: Single measures do not fully discriminate basal levels of hormones from state fluctuations (e.g., situational reactiviy, diurnal rhythm), while high-intensity repeated measurement is costly and burdensome to participants. The proposed research aims to overcome this barrier to research progress by using cutting-edge technology to measure accumulated T in hair. Hair T represents a 3-month hormonal accumulation and thus reflects chronic individual differences un- confounded with state fluctuations but sensitive to pubertal changes. We will examine the interplay between T and genetic influences on alcohol use in a sample of 500 twins (250 same-sex MZ and DZ pairs) ages 13-18. We will collect data on (1) T in saliva and hair, (2) reward sensitivity using a battery of in-lab behavioral tasks and self-report surveys, and (3) alcohol use using youth-report, parent-report, and school disciplinary records. This approach will address the following specific aims: (1) investigate the measurement of T in hair as a novel method that captures the underlying genetic "signal" better than salivary T, (2) examine T as an endophenotype that mediates genetic influences on alcohol use through its effects on reward sensitivity, and (3) examine T as a moderator of genetic influences on reward sensitivity and alcohol use (i.e., gene x hormone interaction). We hypothesize that accumulation of T in hair will represent a highly heritable endophenotype that both mediates and moderates genetic influences on alcohol use, with genetic risk being exacerbated in high T individuals. We also hypothesize that there will be sex differences in the gene > hormone > behavior links, with stronger associations evident in males than females, thus contributing to the emerging sex difference in alcohol use phenotypes. Given the novelty of measuring sex steroids in hair and the potential to illuminate genetic and epigenetic mechanisms underlying adolescent alcohol use, the project is both high-risk and high- reward, and is thus perfectly suited for the R21 mechanism.

说明(申请人提供)：青春期是酒精使用开始和升级的关键时期，也是酒精使用中出现性别差异的关键时期。这项拟议的研究将测试青春期睾酮(T)的变化如何与遗传因素对酒精使用和相关冒险行为的发展产生影响。从童年到青春期，T水平急剧上升，尤其是在男性。青少年T的增加会影响大脑的结构和功能，包括对奖励的神经反应。此外，行为研究发现，T的个体差异预示着酒精使用的表型，男孩比女孩有更强的相关性。一项基本独立的行为遗传学研究已经证实，在青春期过程中，遗传对物质使用和相关冒险行为的影响会增加。这些遗传影响如何与青春期激素变化相交尚不清楚，因为内分泌测量和行为遗传数据很少被整合在一起。这一差距的部分原因是与测量唾液中的激素有关的方法学挑战：单一的测量不能完全区分基础激素水平和状态波动(例如，情景反应性、昼夜节律)，而高强度的重复测量对参与者来说是昂贵和繁重的。这项拟议的研究旨在通过使用尖端技术测量头发中累积的T来克服这一阻碍研究进展的障碍。头发T代表3个月的荷尔蒙积累，因此反映了长期的个体差异，不受状态波动的影响，但对青春期的变化很敏感。我们将在500对13-18岁的双胞胎样本(250对同性MZ和DZ)中，研究T和遗传对酒精使用的影响之间的相互作用。我们将收集关于(1)唾液和头发中T的数据，(2)使用 一组实验室内行为任务和自我报告调查，以及(3)青少年饮酒-报告， 家长报告和学校纪律记录。这一方法将解决以下具体目标：(1)研究头发中T的测量作为一种新的方法，它比唾液T更好地捕捉潜在的遗传“信号”，(2)检查T作为一种内在表型，通过其对奖励敏感性的影响来中介遗传对酒精使用的影响，以及(3)检查T作为遗传影响奖励敏感性和酒精使用(即，基因x激素交互作用)的调节因素。我们假设，T在头发中的积累将代表一种高度可遗传的内表型，既中介又缓和了对饮酒的遗传影响，高T个体的遗传风险会加剧。我们还假设，在基因&激素和行为联系上会有性别差异，男性比女性更明显地存在更强的关联，因此导致了酒精使用表型的性别差异。考虑到测量头发中性类固醇的新颖性，以及阐明青少年饮酒背后的遗传和表观遗传机制的可能性，该项目既有高风险又有高回报，因此非常适合R21机制。