Data-Driven Exploration of Exposomic Influences on the Onset of Alcohol Use During Adolescence

项目总结/摘要 在美国，未成年人饮酒是一个严重的公共卫生问题。早期饮酒（<15岁）， 与那些开始饮酒较晚的人相比，患酒精使用障碍的风险增加了7倍。 因此，全面了解与早期饮酒发病相关的生物心理社会因素， 对解决这个问题至关重要。为此，进行了广泛的研究， 确定了与未来饮酒有关的遗传因素，如酗酒家族史和高多基因遗传， 责任。有限的遗传学研究范围带来了重大挑战，包括（1）主要包括 欧洲血统的参与者，（2）排除早期饮酒者，（3）不清楚 临床适用性。这就需要探索非遗传环境暴露（即， 与酒精使用发作有关。因此，拟议的研究旨在利用来自高度 动力和国家多样性队列，青少年大脑认知发展研究（ABCD; n = 11，000， 9-10岁），并使用一种新的XWAS（eXposome-Wide Association Studies）方法来识别 酒精使用开始时的酒精组学风险因素和衍生的PolyeXtrans酒精风险评分（PXARS） 14岁以下的青少年。PXARS的性能将以这些已建立的遗传学指标为基准， 危险因素此外，酒精使用发作的风险与抑制控制不良有关;因此， 该项目将全面研究预期饮酒的神经生物学和行为相关性 使用来自停止信号任务（SST）的数据的起始。研究还表明，经济因素可能会影响 抑制控制发展;因此，本研究旨在揭示神经行为之间的关联， 因素、PXARS和酒精使用发作。与研究基因组不同，研究基因组可以 调查整个环境（即，自然的，建造的，和社会的），以揭示潜在的临床 可操作的目标。虽然许多基因组学预测因子可能不容易修改（例如，种族偏见， 社会经济障碍），但仍然值得仔细检查;其他预测因素（例如，同龄人、饮食和活动）可以 作为可行的预防和干预目标，以预防和尽量减少青年人的酒精使用。拟议 研究为申请人提供了一个强大而全面的培训计划，其中包括深入的指导， 大数据和生物信息学方法，以及基于任务的功能磁共振成像技术，将大大加强 申请人的技能。申请人将获得来自高技能赞助商团队的特殊支持， 在物质使用神经生物学、神经组学领域具有丰富经验的顾问， 神经成像此外，这项研究将在伊坎医学院进行，这是一个世界著名的 提供顶级培训，课程和机构资源的机构，包括但不限于 成瘾研究所，研究所的Exposomic研究，和高性能计算核心，使之成为 这是执行拟议研究的理想环境。

Project Summary/Abstract Underage drinking in the US is a serious public health concern. Early onset of alcohol use (<15 years old), increases the risk of developing alcohol use disorder by seven times compared to those who start drinking later. Therefore, a comprehensive understanding of biopsychosocial factors associated with early alcohol use onset in adolescence is crucial to address this problem. To this end, extensive studies have been conducted and have identified genetic factors linked to future alcohol use, such as family history of alcoholism and higher polygenic liability. The limited scope of genetic studies poses significant challenges including the (1) primary inclusion of participants of European ancestry, (2) exclusion of those in the early stages of alcohol use, and (3) unclear clinical applicability. This necessitates the need for exploring non-genetic environmental exposures (i.e., exposome) associated with alcohol use onset. As such, the proposed study aims to leverage data from the highly powered and nationally diverse cohort, the Adolescent Brain Cognitive Development Study (ABCD; n = 11,000, 9-10-year-olds), and use a novel eXposome-Wide Association Studies (XWAS) approach to identify exposomic risk factors and derive PolyeXposure Alcohol Risk Scores (PXARS) for alcohol use onset in adolescents up to age 14. The performance of PXARS will be benchmarked against these established genetic risk factors. Furthermore, the risk for alcohol use onset is linked to poor inhibitory control; thus, this proposed project will comprehensively examine the neurobiological and behavioral correlates of prospective alcohol use onset using data from the Stop Signal Task (SST). Studies also suggest that exposomic factors may influence inhibitory control development; therefore, this study aims to uncover associations between neurobehavioral factors, PXARS, and alcohol use onset. Unlike studying the genome, examining the exposome allows for investigating the totality of the environment (i.e., natural, built, and social) to uncover potentially clinically actionable targets. While many exposomic predictors may not be easily modifiable (e.g., racial biases, socioeconomic barriers) but still warrant close examination; other predictors (e.g., peers, diet, and activities) may be viable prevention and intervention targets for preventing and minimizing alcohol use in youth. The proposed study offers the applicant a robust and comprehensive training program, which includes in-depth instruction on big data and bioinformatics approaches, as well as task-based fMRI techniques and will significantly strengthen the applicant's skillset. The applicant will receive exceptional support from a team of highly skilled sponsors and consultants who have extensive experience in the fields of substance use neurobiology, exposomics, and neuroimaging. Furthermore, the research will be conducted at the Icahn School of Medicine, a world-renowned institution that offers top-tier training, coursework, and institutional resources including but not limited to the Addiction Institute, the Institute for Exposomic Research, and the High-Performance Computing Core, making it an ideal setting for executing the proposed study.