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.

描述（由申请人提供）：青春期是饮酒的开始和升级以及饮酒中性别差异的出现的关键时期。拟议的研究将测试青春期期间睾丸激素（T）的变化如何与遗传影响对酒精使用和相关冒险行为的发展相互作用。从童年到青春期，尤其是男性，T水平急剧增加。青少年增加T会影响大脑结构和功能，包括对奖励的神经反应。此外，行为研究发现，t的个体差异可以预测酒精使用表型，男孩中的关联比女孩更强。行为遗传研究的主要独立流已经确定，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期间的荷尔蒙变化相交，因为内分泌测量和行为遗传数据很少被整合。该差距部分是由于与测量唾液中的激素相关的方法论挑战：单一措施并不能完全区分基础荷尔蒙与状态波动（例如，情境重新反应，昼夜节奏），而高强度重复的测量是代价和昂贵的，对参与者是昂贵的。拟议的研究旨在通过使用尖端技术来测量头发中的T来克服这一研究进度的障碍。头发T代表了3个月的激素积累，因此反映了与状态波动混淆但对青春期变化敏感的慢性个体差异。我们将在13-18岁的500个双胞胎（250个同性MZ和DZ Pairs）样本中检查T与遗传影响对酒精使用的相互作用。我们将收集有关唾液和头发（1）T的数据，（2）使用 一系列LAB内行为任务和自我报告调查，以及（3）使用青少年报告的酒精， 家长报告和学校纪律记录。这种方法将解决以下具体目的：（1）研究头发中T的测量作为一种新方法，一种新方法，它比唾液t更好地捕获了遗传“信号”，（（2）将T作为一种内表型，通过对奖励敏感性的影响以及（3）对遗传的影响进行奖励的影响（I。我们假设T中T的积累将代表一种高度可遗传的内表型，既可以介导并缓解对饮酒的遗传影响，并且在高T个体中遗传风险加剧了。我们还假设，基因>激素>行为联系将存在性别差异，在男性中比女性更明显的关联，从而导致在酒精使用表型中出现的性别差异。鉴于测量头发中的性类固醇的新颖性以及阐明青少年饮酒潜在的遗传和表观遗传机制的潜力，该项目既是高风险又高奖励，因此非常适合R21机制。