EARLY SUBSTANCE USE AND ADDICTION: GENES, ENVIRONMENT, AND EPIDEMIOLOGY

描述（由申请人提供）：该项目的全球目标是在R21探索/发展机制下提出的，旨在研究物质依赖的遗传因素与开始饮酒或吸烟的年龄之间的相互作用，同时通过描述性和准实验性流行病学研究推进我们对这些变量在成瘾中的作用的理解。酒精和烟草使用的早期发作是强烈的，潜在的可改变的成瘾风险因素，了解其影响发挥的关键可改变途径符合公共卫生的最佳利益。这种应用的遗传方面是由动物模型中的神经生物学研究激发的，这些研究表明青春期是物质依赖发展的关键时期。我们将利用4000多名受试者的遗传信息病例对照样本的现有数据来验证这样的假设，即开始使用物质的年龄会调节某些成瘾易感基因在赋予成瘾责任方面的影响。这一应用的流行病学方面受到我们小组最近研究的启发，这些研究记录了酒精依赖的长期趋势，特别是女性，这与饮酒年龄的历史变化密切相关。由于这些变化发生在饮酒年龄法律变化期间，我们建议调查最低法定饮酒年龄（MLPA’s）作为成年后期酒精和药物依赖的风险因素的可能作用。我们还将调查寿命和目前对其他滥用药物依赖的长期趋势。这些流行病学研究将使用来自全国酒精纵向流行病学调查的现有数据，并将审查全国酒精及相关疾病流行病学调查。每项调查都有超过4万名受试者的数据。这两项相隔十年的调查具有可比性，因此可以对长期趋势进行详细分析，而且各州标识符的可用性使得可以将州一级的饮酒年龄政策作为“自然实验”，通过早期饮酒途径影响长期饮酒和吸毒模式。对潜在的基因-环境相互作用和环境主要影响的协调研究将进一步阐明这些风险因素与成瘾之间的病因学联系，并可能有助于确定由人口统计学群体或遗传风险水平定义的个人亚群体，他们最有可能从旨在延迟物质使用的干预措施中受益。公共卫生相关性：物质使用障碍是当今美国可预防的早期死亡的主要原因之一。药物使用的早期发作是常见成瘾的一个强大且具有潜在延展性的风险因素。该项目旨在通过检查基因-环境相互作用和直接环境影响与早期物质使用和物质使用障碍之间的关联，进一步阐明延迟物质使用的潜在益处和局限性。

DESCRIPTION (provided by applicant): The global aim of this project, proposed under the R21 exploratory/developmental mechanism, is to examine the interplay between genetic factors for substance dependence and the age at onset of drinking or smoking, while advancing our understanding of the role of these variables in addiction through descriptive, and quasi- experimental, epidemiological studies. Early onsets of alcohol and tobacco use are strong, potentially modifiable risk factors for addiction, and it is in the best interest of public health to understand the key modifiable pathways by which their influence is exerted. The genetic aspect of this application is motivated by neurobiological studies in animal models that suggest adolescence as a critical period of vulnerability for the development of substance dependence. We will take advantage of existing data from a genetically informative case-control sample of over 4,000 subjects to test the hypothesis that age at onset of substance use moderates the effects of some addiction susceptibility genes in conferring liability to addiction. The epidemiological aspect of this application is motivated by recent studies from our group, which have documented secular trends in alcohol dependence, particularly among women, that correspond closely to historical changes in age-at-onset of drinking. Because these changes occurred during periods of changing drinking-age laws, we propose to investigate the possible role of minimum legal alcohol purchase ages (MLPA's) as a risk factor for alcohol and drug dependence in later adulthood. We will also investigate secular trends in lifetime and current dependence on other drugs of abuse. These epidemiological studies will use existing data from the National Longitudinal Alcohol Epidemiologic Survey and the National Epidemiological Survey on Alcohol and Related Conditions will be examined. Each survey has data on over 40,000 subjects. The comparability of the two surveys, spaced ten years apart, allows for detailed analyses of secular trends, and the availability of state identifiers makes it possible to use state-level drinking age policies as a 'natural experiment' that may have influenced long-term alcohol and drug use patterns through early alcohol use pathways. The coordinated study of potential gene-environment interactions and environmental main effects together will shed further light on the etiological link between these risk factors and addiction, and may help identify sub-groups of individuals, defined by demographic group or genetic risk level, who would be most likely to benefit from interventions aimed at delaying substance use. PUBLIC HEALTH RELEVANCE: Substance use disorders are among the top contributors to preventable early mortality in the United States today. Early onset of substance use is a strong and potentially malleable risk factor for common addictions. This project aims to shed further light on the potential benefits and limitations of delaying substance use by examining both gene-environment interactions and direct environmental influences in relation to the association between early substance use and substance use disorders.