Pathways to Alcohol Use Disorders in ALSPAC: A Genetic-Developmental Study

描述（由申请人提供）：ALSPAC中酒精使用障碍的途径：一项遗传发育研究酒精使用障碍（AUDs）来自不同的遗传和环境风险因素，通过一系列复杂的发育途径发挥作用。很少有研究能够在所需的年龄范围内结合样本量、代表性以及足够频繁和详细的评估，从而为解开这些复杂的病因学途径提供现实的机会。雅芳家长和孩子纵向研究（ALSPAC）就是这样一个研究。ALSPAC项目从雅芳英格兰地区确定的13 000多名孕妇开始，在过去16年里对这一样本进行了详细的跟踪调查。样本现在正进入从青春期到青年期的关键过渡期。这份申请由来自弗吉尼亚联邦大学和布里斯托大学的一组研究人员准备，在ALSPAC队列中有三个具体目标。第一个目标是在已经计划在18岁和20岁时进行的问卷调查中增加对酒精使用和AUD症状的详细评估。这将使我们能够捕捉到酒精使用的关键发展阶段和AUD早期症状的出现。第二个目的是进行一系列广泛的分析，寻求了解酒精使用（Au）和酒精使用问题（AUPs）的病因学途径。这些分析的具体目标是：（1）描述青春期Au和AUPs的模式;（2）识别预测青春期Au和AUPs的儿童期风险因素，并了解这些风险展开的发展过程;（3）研究这些风险因素在青春期的进一步发展及其与新出现的Au及其后果的相互作用;（4）测试性别对与Au和AUPs相关的模式、预测因子和发育过程的调节作用;（5）使用目标1下收集的18岁和20岁数据，将Au和AUPs的风险模型扩展到青年期。这些分析将研究风险如何在三个主要领域的发展中展开：外部化，内部化和环境（以及这些最终如何与Au和AUPs的发展相关）。每个领域都很广泛，项目的目标之一是分析这些结构并描述最相关的风险维度。该项目的第三个目标是将关于一组有限的先前验证的风险基因的信息纳入目标2中开发的Au、AUPs和AUDs的风险发育模型中。这将使用来自ALSPAC队列的至少3，000名受试者的分子遗传数据来完成，NIH无需支付任何费用。这些分析将使我们能够研究有助于Au和AUPs风险（和弹性）途径的生物，心理和社会过程的动态相互作用。 由于其大样本量、代表性、详细和频繁的表型评估以及基因型数据的可用性，ALSPAC队列提供了一个独特的机会，可以在发育背景下阐明AUD的易感性和保护因素的复杂网络。

DESCRIPTION (provided by applicant): Pathways to Alcohol Use Disorders in ALSPAC: A Genetic-Developmental Study Alcohol Use Disorders (AUDs) emerge from diverse genetic and environmental risk factors acting through a range of complex developmental pathways. Very few studies exist that have a combination of sample size, representativeness, and sufficiently frequent and detailed assessments over the requisite age range to provide a realistic opportunity to disentangle these intricate etiologic pathways. The Avon Longitudinal Study of Parents and Children (ALSPAC) is such a study. Beginning with over 13,000 pregnant mothers ascertained around Avon England, the ALSPAC project has conducted detailed follow-ups of this sample for the last 16 years. The sample is now entering the critical transitional period from adolescence to young adulthood. This application, prepared by a team of investigators from Virginia Commonwealth University and University of Bristol, has three specific aims in the ALSPAC cohort. The first aim is to add detailed assessments of alcohol use and symptoms of AUDs to questionnaires already scheduled to occur at ages 18 and 20. This will allow us to capture a key developmental phase for alcohol use and the emergence of early symptoms of AUDs. The second aim is to conduct an extensive series of analyses seeking to understand the etiologic pathways to alcohol use (AU) and alcohol use problems (AUPs). The specific goals of these analyses will be (1) to characterize patterns of AU and AUPs across adolescence; (2) to identify childhood risk factors that predict AU and AUPs in adolescence and to understand the developmental processes by which these risks unfold; (3) to study the further development of these risk factors across adolescence and their interaction with emerging AU and its consequences; (4) to test the moderating role of gender on patterns, predictors, and developmental processes related to AU and AUPs; and (5) to extend models of risk for AU and AUPs into young adulthood using the age 18 and 20 data collected under Aim 1. The analyses will examine how risk unfolds across development across three major domains: Externalizing, Internalizing, and Environment (and how these eventually relate to AU and the development of AUPs). Each of these domains is broad, and one of the goals of the project will be to parse these constructs and delineate the most relevant risk dimensions. The third aim of the project is to incorporate information about a limited set of previously validated risk genes into developmental models of risk for AU, AUPs, and AUDs developed in Aim 2. This will be accomplished using molecular genetic data available on at least 3,000 subjects from the ALSPAC cohort at no cost to NIH. These analyses will allow us to study the dynamic interplay of biological, psychological, and social processes that contribute to pathways of risk (and resiliency) for AU and AUPs. With its large sample size, representativeness, detailed and frequent phenotypic assessments and availability of genotypic data, the ALSPAC cohort provides a unique opportunity to clarify, in a developmental context, the complex web of susceptibility and protective factors for AUDs.