Environment, Genes, and Temperament on the Development of Alcohol Use Disorder

 描述（由申请人提供）：有害酒精消费是美国可预防死亡的第三大原因。1在18岁之前使用酒精的人中，四分之一会上瘾，而在21岁开始使用酒精的人中，每25人中就有一人会上瘾。2因此，识别酒精使用的早期前兆可能会延迟饮酒的发生，并有助于最大限度地降低酒精使用障碍（AUD）的风险。迄今为止的研究主要集中在基因与AUD之间的直接关联，在遗传途径、相关社会背景以及AUD病因学基础上的基因与环境（GxE）之间的相互作用方面存在关键空白。候选人的长期目标是：1）通过发展知情的跨学科研究，更好地了解影响AUD发病和病因的机制; 2）将这些知识转化为研究，这将独特地有助于更机械知情的预防规划的发展。拟议的K 08指导临床科学家研究职业发展奖旨在解决两个直接目标。第一个是纠正这些差距，在AUD文献中，推进跨学科的研究计划的遗传，社会环境和气质因素的基础上，青少年饮酒使用两个大型纵向数据集。目标1将把性状（气质，问题行为）作为间接的发展标记在AUD的潜在基因的表达。目标2将使用高质量的测量方法，采用新的方法，对社会背景进行更知情的评估。目标3将评估不同形式的潜在GxE相互作用（素质-应激、差异易感性、Vantage敏感性）对AUD的影响。第二个直接目标是提高候选人的知识基础和研究技能。候选人计划概述了四个培训目标：1）扩展基因分型和分子遗传学的知识; 2）发展生物统计学原理和方法的技能; 3）增加复杂研究设计的统计方法的知识; 4）获得负责任的研究行为的额外培训。该培训将通过测试更全面的AUD发展机制配方（包括遗传信息）来推进候选人之前检查AUD发作风险因素的工作。它还将建立她的跨学科研究计划，作为影响青少年酒精使用的机械过程的独立调查员，导致K 08奖期内的R 01资金。该项目将利用两项前瞻性纵向研究，密歇根州纵向研究（MLS）和国家青少年健康纵向研究（Add Health）作为复制样本。这些数据集在收集广泛领域、各种报告者和多代人的信息方面是独一无二的。数据包括心理，社会环境，认知，气质和遗传因素。很少有联合收割机纵向研究结合大样本量，遗传和全面的心理社会数据，并详细和频繁的评估，在整个生命周期。这使得独特的方法的机会，以测试复杂的社会环境和基因的动态相互作用，以及气质和问题行为的作用，作为中介之间的关联靶基因和AUD在一个前瞻性的发展框架。候选人将通过成瘾，精神遗传学，生物统计学，气质和纵向研究设计领域的知名专家的指导和合作，通过教学和研究项目完成来实现这些培训目标（Robert Zucker博士，Margit Burmeister，Kerby Shedden和Joel Nigg）。密歇根大学丰富的资源也将支持她的跨学科研究计划，并促进她过渡到一个独立的 研究青少年AUD。这种创新的应用程序解决了国家酒精滥用和酒精中毒研究所（NIAAA）的使命在最近的战略计划中概述：1）需要广泛的调查分析; 2）具有较强的定量技能的研究人员;和3）跨学科的研究团队。像MLS和Add Health这样的全面纵向数据集是罕见的;这些数据集可以检查基因，气质，社会背景，非特异性风险因素的发育过程，以及它们在发育过程中对AUD的相互作用。此外，使用潜变量来可靠地表示GxE交互中的社会背景是新颖的。这种方法允许高质量的测量社会影响青少年AUD跨适应性和不利的背景。最后，该项目将利用候选人在定量训练，发展精神病理学和成瘾方面的背景，形成跨学科的伙伴关系。这种多学科的方法将产生一个全面的调查基因，气质和社会背景的作用，反映了青少年AUD的发病和病程的复杂性。只有通过这些跨学科的团队，才能实现遗传学研究对AUD的最大影响。

 DESCRIPTION (provided by applicant): Harmful alcohol consumption is the third leading cause of preventable death in the nation.1 Among those using alcohol before the age of 18, 1 in 4 will become addicted, compared to 1 in 25 who start using at age 21.2 As such, identification of early precursors to alcohol use may delay the onset of drinking and help minimize risk for alcohol use disorder (AUD). Research to date focuses on direct associations between genes and AUD, leaving critical gaps regarding genetic pathways, relevant social contexts, and interactions between genes and the environment (GxE) underlying the etiology of AUD. The candidate's long-term goals are to: 1) achieve a greater understanding of the mechanisms influencing the onset and cause of AUD through developmentally informed interdisciplinary research; and 2) translate this knowledge into research that will uniquely contribute to the development of more mechanistically informed prevention programming. The proposed K08 Mentored Clinical Scientist Research Career Development Award seeks to address two immediate goals. The first is to redress these gaps in the AUD literature by advancing an interdisciplinary program of research on genetic, social environmental and temperamental factors underlying adolescent alcohol use using two large longitudinal datasets. Aim 1 will incorporate traits (temperament, problem behavior) as indirect developmental markers in the expression of underlying genes on AUD. Aim 2 will use high quality measurement using novel methodologies to capture a more informed assessment of social contexts. Aim 3 will assess different forms of latent GxE interactions (diathesis-stress, differential susceptibility, vantage sensitivity) on AUD. The second immediate goal is to enhance the candidate's knowledge base and research skills. The candidate plan outlines four training objectives: 1) extends knowledge in genotyping and molecular genetics; 2) develop skills in biostatistical principles and methods; 3) increase knowledge of statistical approaches for complex study designs; and 4) gain additional training in the responsible conduct of research. This training will advance the candidate's prior work examining risk factors of AUD onset by testing more comprehensive mechanistic formulations of the development of AUD by including genetic information. It will also establish her interdisciplinary program of research as an independent investigator in mechanistic processes impacting adolescent alcohol use, leading to R01 funding within the K08 award period. The project will utilize two prospective longitudinal studies, the Michigan Longitudinal Study (MLS) and The National Longitudinal Study of Adolescent Health (Add Health), as a replication sample. These datasets are unique in gathering information across extensive domains, various reporters, and multiple generations. Data include psychological, social environmental, cognitive, temperamental, and genetic factors. Few longitudinal studies combine large sample sizes, genetic and comprehensive psychosocial data, and detailed and frequent assessments over the lifespan. This allows for unique methodological opportunities to test the dynamic interplay of complex social environments and genes, and the role of temperament and problem behavior as mediators in the association between targeted genes and AUD within a prospective developmental framework. The candidate will meet these training objectives via didactics and research project completion through the mentorship and collaboration of renowned experts in the field of addiction, psychiatric genetics, biostatistics, temperament, and longitudinal study designs (Drs. Robert Zucker, Margit Burmeister, Kerby Shedden, and Joel Nigg). The rich resources available at the University of Michigan will also support her interdisciplinary program of research and facilitate her transition into an independent investigator examining adolescent AUD. This innovative application addresses the National Institute of Alcohol Abuse and Alcoholism's (NIAAA) mission as outlined in the most recent Strategic Plan: 1) the need for broad-based survey analysis; 2) researchers with strong quantitative skills; and 3) interdisciplinary research teams. Comprehensive longitudinal datasets such as the MLS and Add Health are rare; these datasets make it possible to examine the developmental course of genes, temperament, social contexts, non-specific risk factors, and their interplay on AUD across development. Moreover, the use of latent variables to reliably represent social contexts in GxE interactions is novel. This methodology allows for high-quality measurement of social influences impacting adolescent AUD across adaptive and adverse contexts. Lastly, the project will capitalize on the candidate's background in quantitative trainin, developmental psychopathology, and addiction to form an interdisciplinary partnership. This multidisciplinary approach will generate a comprehensive investigation in the role of genes, temperament, and social contexts reflecting the complexity inherent in the onset and course of adolescent AUD. It is only through these interdisciplinary teams that the maximal impact of genetics research on AUD can be realized.