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

第一次喝酒的年龄和酗酒：基因和环境的交叉

• 批准号: 8728701
• 负责人: ARPANA AGRAWAL
• 金额: $ 21.19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728701
• 关键词: Accounting; Address; Adolescent; Adult; Age; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Awareness; Behavioral; Biological; Birth; Candidate Disease Gene; Data; Data Analyses; Data Set; Development; Environment; Environmental Risk Factor; Epidemiology; Etiology; Female; Figs - dietary; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Grant; Image; Individual; Intoxication; Link; Measures; Mediating; Meta-Analysis; Methods; Modeling; Molecular; Morbidity - disease rate; Nature; Neurobiology; Neurologic; Oranges; Outcome; Play; Predisposition; Preventive Intervention; Psychopathology; Public Health; Research; Resistance; Risk; Risk Factors; Role; Route; Sampling; Shapes; Single Nucleotide Polymorphism; Twin Multiple Birth; Ursidae Family; Virulent; Work; alcohol effect; alcohol exposure; alcohol related problem; alcohol risk; alcohol use disorder; career; cohort; drinking; early alcohol use; early drinking; early onset; genetic variant; genome-wide; indexing; innovation; insight; male; meetings; minimum drinking age; mortality; neurobiological mechanism; novel; programs; prospective; public health relevance; theories; vehicular accident

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.

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。在与AUD的责任最突出的相关性中，最重要的是第一饮料（AFD）和其他饮酒里程碑，例如刚中毒时的年龄（AFI）和初期常规饮酒（AFR）年龄（AFR）。早期发作的饮酒者在随后的酒精有关问题，AUD和其他相关危害（例如机动车事故）的几率增加2-6。尽管对AFD与AUD之间的联系有很大的支持，但该关联的基础机制仍然有争议，重要的是，对这种关系的基因信息有限。可以提出多种遗传信息的假设来解释这种关系：（a）AFD和AUDS与遗传和环境因素重叠的病因共享了病因； （b）AFD对AUDS有因果影响（在考虑共同病因之后）；最近，（c）即使考虑了共同的病因，AFD也会节省可遗传的影响对auds的作用。这些假设中的每一个都具有独特的公共卫生影响，并且了解哪些机制在AUDS的病因中起着最重要的作用，这将在未来的预防和干预工作中具有重要的信息，目的是减轻早期AFD的负担。统一这些竞争假设的一种方法是基因环境相互作用，包括基因环境相关性和相互作用。在此二次数据分析R21中，我们使用潜在（基因组）现有的遗传信息数据，即AFD，AFI，AFI，AFR和AUDS之间的链接检查。具体目的是：（a）使用双数据，通过AFD，AFI和AFR修改影响AUD的可遗传因素的程度； （b）检查在考虑了共享病因后，AFD，AFI和AFR中度（即基因X环境相互作用或GXE）是否单独和作为多基因风险评分的候选基因变异的程度，影响AUD； （c）以探索性的方式使用全基因组关联数据，以通过GXE确定与AUD相关的新型遗传多态性，作为AFD，AFI和AFR的函数。该提案的优势包括使用多个双胞胎数据集，代表不同的和重叠的人群，包括男性和女性，这将使我们能够验证来自不同培养物和出生队列中的样本的跨样本，独立的样本，用于对候选基因和基因组的单个SNP和多基因分数的荟萃分析。该R21的结果将用于开发一项研究计划，以对可能与早期暴露于酒精有关的分子，细胞和神经生物学机制进行研究。从公共卫生的角度来看，该提案的结果可以通过识别AFD，AFI和AFR影响到AUDS的路线来为减少饮酒和AUD的过渡和AUD的策略提供信息。