AGE AT FIRST DRINK AND ALCOHOLISM: INTERSECTION OF GENES AND ENVIRONMENT

描述（由申请人提供）：酒精使用障碍与相当大的发病率和死亡率相关。与AUD易感性最显著的相关性是首次饮酒年龄（AFD）和其他饮酒里程碑，如首次醉酒年龄（AFI）和首次定期饮酒年龄（AFR）。早发性饮酒者随后出现酒精相关问题、AUD和其他相关伤害（例如机动车事故）的几率增加2-6。尽管AFD和AUD之间的联系得到了压倒性的支持，但这种关联的机制仍然存在争议，重要的是，这种关系的遗传信息研究有限。可以假设多个遗传信息假说来解释这种关系：（a）AFD和AUD具有共同的病因，具有重叠的遗传和环境因素;（B）AFD对AUD具有因果影响（在考虑共同的病因后）;最近，（c）即使在考虑共同的病因后，AFD也会调节遗传影响对AUD的作用。这些假设中的每一个都具有独特的公共卫生意义，并且了解哪些机制在AUD的病因学中起着最突出的作用，这将在未来针对减轻早期AFD负担的预防和干预工作中提供大量信息。统一这些相互竞争的假说的一种方法是基因-环境相互作用，包括基因-环境相关和相互作用。在这个次要数据分析R21中，我们使用潜在的（双胞胎）和测量的（基因组）现有遗传信息数据，研究AFD，AFI，AFR和AUD之间的联系。具体目标是：（a）使用双胞胎数据确定影响AUD的遗传因素被AFD、AFI和AFR改变的程度;（B）检查在考虑共同病因后，AFD、AFI和AFR是否为中度（即基因x环境相互作用，或GxE）候选基因变异（单独和作为多基因风险评分）影响AUD的程度;以及（c）以探索性的方式使用全基因组关联数据，通过GxE，作为AFD、AFI和AFR的函数来鉴定与AUD相关的新的遗传多态性。该提议的优点包括使用多个双胞胎数据集，代表不同的和重叠的队列，包括男性和女性，这将使我们能够在来自不同文化和出生队列的样本中验证我们的发现，这些样本是用于对来自候选基因和全基因组关联分析的单SNP和多基因评分进行荟萃分析的独立样本。R21的结果将用于制定一项研究计划，研究可能与早期暴露于酒精有关或被其破坏的分子，细胞和神经生物学机制。从公共卫生的角度来看，该提案的结果可以通过确定AFD，AFI和AFR影响AUD脆弱性的途径，为减少向问题饮酒和AUD过渡的战略提供信息。

DESCRIPTION (provided by applicant): Alcohol use disorders are associated with considerable morbidity and mortality. Amongst the most prominent correlates of liability to AUDs is age at first drink (AFD) and other drinking milestones, such as age at first intoxication (AFI) and age at first regular drinking (AFR). Early-onset drinkers are at 2-6 increased odds of subsequent alcohol-related problems, AUDs and other related harms (e.g. motor vehicle accidents). Despite overwhelming support for a link between AFD and AUDs, the mechanism underlying the association remains controversial and, importantly, genetically informative studies of this relationship are limited. Multiple genetically-informative hypotheses can be posited to explain this relationship: (a) AFD and AUDs have shared etiologies with overlapping genetic and environmental factors contributing to them; (b) AFD has a causal influence on AUDs (after accounting for shared etiologies); and more recently, (c) even after accounting for shared etiologies, AFD moderates the role of heritable influences on AUDs. Each of these hypotheses bear unique public health implications and understanding which mechanisms play the most prominent role in the etiology of AUDs would be substantially informative in future prevention and intervention efforts targeted at reducing the burden of early AFD. One approach that unifies these competing hypotheses is that of gene- environment interplay, including gene-environment correlation and interaction. In this secondary data analysis R21, we examine, using latent (twin) and measured (genomic) existing genetically informative data, the links between AFD, AFI, AFR and AUDs. The specific aims are: (a) to identify using twin data, the extent to which heritable factors influencing AUD are modified by AFD, AFI and AFR; (b) to examine whether after accounting for shared etiologies, AFD, AFI and AFR moderate (i.e. gene x environment interaction, or GxE) the extent to which candidate gene variants, both individually and as a polygenic risk score, influence AUD; and (c) to use genomewide association data, in an exploratory fashion, to identify novel genetic polymorphisms associated with AUD, via GxE, as a function of AFD, AFI and AFR. The strengths of this proposal include the use of multiple twin datasets, representing distinct and overlapping cohorts and including both males and females, which will allow us to validate our finding across samples from different cultures and birth cohorts, independent samples for meta-analysis of single SNP and polygenic scores from candidate gene and genomewide association analyses. Results from this R21 will be used to develop a program of research into the molecular, cellular and neurobiological mechanisms that may be associated with or disrupted by early exposure to alcohol. From a public health perspective, results from this proposal can inform strategies for reducing transitions to problem drinking and AUDs by identifying the routes through which AFD, AFI and AFR impact vulnerability to AUDs.