Testing Gene-Testosterone Interplay in Adolescent Alcohol Use

描述（由申请人提供）：青春期是酒精使用的开始和升级以及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)的变化如何与基因对酒精使用和相关冒险行为发展的影响交叉。从童年到青春期，T水平急剧上升，尤其是男性。青少年时期T的增加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的个体差异预测了酒精使用表型，男孩比女孩的相关性更强。一项很大程度上独立的行为遗传学研究已经证实，基因对物质使用和相关冒险行为的影响在青春期期间会增加。由于内分泌测量和行为遗传数据很少被整合，这些遗传影响如何与青春期激素变化交叉尚不清楚。这一差距部分是由于与测量唾液中的激素相关的方法挑战：单一测量不能完全区分激素的基础水平和状态波动（例如，情境反应性，昼夜节律），而高强度的重复测量对参与者来说成本高昂且负担沉重。该研究旨在利用尖端技术测量头发中积累的T，从而克服这一研究进展的障碍。毛发T代表3个月的激素积累，因此反映了与状态波动无关的慢性个体差异，但对青春期的变化很敏感。我们将在500对年龄在13-18岁的双胞胎（250对同性MZ和DZ）样本中研究T和基因对酒精使用的影响之间的相互作用。我们将收集(1)唾液和毛发中的T，(2)使用a的奖励敏感性数据

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.