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有关。与AUDS易感性最显著的相关因素是首次饮酒年龄(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与酒精有关的问题、AUDS和其他相关伤害(如机动车事故)的几率增加2-6%。尽管绝大多数人支持AFD和AUDS之间的联系，但这种联系背后的机制仍然存在争议，更重要的是，对这种关系的遗传信息研究有限。可以假设多种遗传信息假说来解释这种关系：(A)AFD和AUD具有共同的病因，导致它们的遗传和环境因素重叠；(B)AFD对AUDS有因果影响(在考虑了共同的病因后)；以及最近，(C)即使在考虑到共同的病因后，AFD仍然调节了可遗传影响对AUD的作用。这些假说中的每一个都具有独特的公共卫生影响，了解哪些机制在AUDS的病因中起着最重要的作用，将在未来旨在减轻早期AFD负担的预防和干预努力中提供大量信息。统一这些相互竞争的假说的一种方法是基因-环境相互作用的方法，包括基因-环境的相关性和相互作用。在这个二次数据分析R21中，我们使用潜在的(孪生的)和测量的(基因组)现有的遗传信息数据，检查AFD、AFI、AFR和AUD之间的联系。具体目的是：(A)利用双胞胎数据确定AFD、AFI和AFR对影响AUD的可遗传因素的修改程度；(B)在考虑共同的病因后，AFD、AFI和AFR是否适度(即基因x环境互作，或GxE)候选基因变异对AUD的影响程度，无论是单独的还是作为多基因风险分数；以及(C)以探索性方式使用全基因组关联数据，以AFD、AFI和AFR的函数通过GxE识别与AUD相关的新的遗传多态。这一建议的优势包括使用多个双胞胎数据集，代表不同和重叠的队列，包括男性和女性，这将使我们能够通过来自不同文化和出生队列的样本、用于单个SNP的Meta分析的独立样本以及来自候选基因和全基因组关联分析的多基因分数来验证我们的发现。来自R21的结果将被用来开发一个研究项目，研究可能与早期接触酒精有关或被破坏的分子、细胞和神经生物学机制。从公共卫生的角度来看，这项提案的结果可以通过确定AFD、AFI和AFR影响AUDS易感性的途径，为减少向问题饮酒和AUDS过渡的战略提供参考。

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.