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

 说明(申请人提供)：有害饮酒是全国可预防死亡的第三大原因。1在18岁之前饮酒的人中，每4人中就有1人会上瘾，而在21.2岁开始饮酒的人中，每25人中就有1人上瘾。因此，识别饮酒的早期前体可能会推迟饮酒的开始，并有助于将酒精使用障碍(AUD)的风险降至最低。到目前为止的研究主要集中在基因和AUD之间的直接联系上，在遗传途径、相关的社会背景以及基因和环境之间的相互作用(GxE)方面留下了关键的空白，这些都是AUD的病因学基础。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发病和原因的机制；以及2)将这些知识转化为研究，这将独特地有助于制定更具机械性的预防规划。拟议的K08临床科学家导师研究职业发展奖旨在解决两个眼前的目标。第一个是通过使用两个大型纵向数据集，推进一个关于青少年饮酒背后的遗传、社会环境和气质因素的跨学科研究计划，以弥补AUD文献中的这些差距。目标1将把特征(气质、问题行为)作为间接发育标记纳入AUD潜在基因的表达中。目标2将使用高质量的测量方法，使用新的方法来获取对社会背景的更知情的评估。AIM 3将评估不同形式的潜在GxE相互作用(素质-应激、差异敏感性、优势敏感性)对AUD的影响。第二个迫在眉睫的目标是增强候选人的知识基础和研究技能。候选计划概述了四个培训目标：1)扩大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)获得负责任的研究操作方面的额外培训。这项培训将通过测试包括遗传信息在内的更全面的AUD发展机制公式，来推进候选人检查AUD发病风险因素的先前工作。它还将建立她作为影响青少年酒精使用的机械过程的独立研究员的跨学科研究计划，从而在K08奖励期内获得R01资金。该项目将利用两项前瞻性纵向研究，密歇根纵向研究(MLS)和国家青少年健康纵向研究(ADD Health)，作为复制样本。这些数据集在收集跨广泛领域、不同记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。很少有纵向研究结合大样本量、遗传和全面的心理社会数据，以及对寿命的详细和频繁的评估。这就提供了独特的方法机会来测试复杂的社会环境和基因之间的动态相互作用，以及气质和问题行为作为中介在预期发展框架内目标基因和AUD之间的关联中的作用。应聘者将通过教学和研究项目完成来实现这些培训目标，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(Robert Zucker博士、Margit Burmeister博士、Kerby Shedden博士和Joel Nigg博士)的指导和合作来实现这些培训目标。密歇根大学丰富的资源也将支持她的跨学科研究计划，并促进她向独立的 调查人员检查青少年澳元。这一创新的应用程序满足了国家酒精滥用和酒精中毒研究所(NIAAA)在最新战略计划中概述的使命：1)需要基础广泛的调查分析；2)具有强大的量化技能的研究人员；3)跨学科研究团队。像MLS和Add Health这样的综合纵向数据集很少见；这些数据集使人们有可能检查基因、气质、社会背景、非特定风险因素的发育过程，以及它们在整个发育过程中对AUD的相互作用。此外，在GxE互动中使用潜在变量来可靠地表示社会背景是新颖的。这一方法允许高质量地衡量影响青少年AUD的社会影响，包括适应环境和不利环境。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，形成跨学科的合作伙伴关系。这种多学科的方法将对基因、气质和社会背景的作用进行全面的调查，反映青少年AUD发病和过程中固有的复杂性。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.