COLLABORATIVE STUDY ON THE GENETICS OF ALCOHOLISM/COGA

描述（由申请人提供）：酒精中毒是一种复杂的疾病，受遗传易感性、环境因素、基因间相互作用以及基因与环境间相互作用的影响。这项提案是对酒精中毒遗传学合作研究（COGA）进行为期五年的更新，这是一项八个地点的国家合作，其总体目标是识别和表征影响酒精依赖和相关表型易感性的基因。这种更新是基于这样一种假设，即某些受遗传影响的易感性差异是酒精中毒所独有的，而另一些涉及额叶功能（冲动性、神经去抑制）的差异则会影响一系列相关结果，包括外化、情绪障碍和滥用其他物质。 COGA已经确定了几个影响酒精中毒发展的基因及其相关表型，包括反映基本神经机制的内表型。我们建议建立在我们成功的策略，结合联合收割机的发展，神经生理和临床/行为的表型与广泛的SNP基因分型和连锁不平衡分析，以确定这些表型的基因，并检查它们影响表型的机制。将对与重要表型密切相关的基因进行功能研究，包括检查潜在的编码和剪接差异以及启动子功能的潜在差异。还提出了一项青少年和年轻人的前瞻性研究，其中将测量新的神经生理学和其他表型，并进行遗传分析。这将有助于进一步了解特定基因的作用，以及它们如何相互作用以及与环境相互作用，以影响酒精中毒和相关表型发展的时间进程。这些组成部分是相互关联的，都有助于识别和理解影响酒精中毒和相关表型的遗传和环境因素的主题，期望这些知识将提出预防和治疗酒精中毒和相关疾病的新方法。

DESCRIPTION (provided by applicant): Alcoholism is a complex disease influenced by genetic susceptibility, environmental factors, and by interactions among genes and between genes and environment. This proposal is for a five-year renewal of the Collaborative Study on the Genetics of Alcoholism (COGA), an eight-site national collaboration with the overarching goal of identifying and characterizing genes that affect the susceptibility to develop alcohol dependence and related phenotypes. This renewal is based on the hypothesis that some of the genetically influenced differences in susceptibility are unique to alcoholism, whereas others, involving frontal lobe function (impulsivity, neural disinhibition) influence a range of related outcomes including externalizing and mood disorders and abuse of other substances. COGA has identified several genes that influence the development of alcoholism and it's correlated phenotypes, including endophenotypes reflecting basic neural mechanisms. We propose to build on our successful strategies that combine the development of neurophysiological and clinical/behavioral henotypes with extensive SNP genotyping and linkage disequilibrium analyses to identify genes underlying those phenotypes and examine mechanisms by which they influence the phenotypes. Functional studies of genes strongly associated with important phenotypes, including examination of potential coding and splicing differences and potential differences in promoter function will be conducted. A prospective study of adolescents and young adults is also proposed in which novel neurophysiological and other phenotypes will be measured and subject to genetic analyses. This will facilitate further understanding of the role of specific genes and how they interact with each other and with the environment to influence the time course of development of alcoholism and related phenotypes. These components are interrelated, and all contribute to the theme of identifying and understanding genetic and environmental factors that affect alcoholism and related phenotypes, with the expectation that this knowledge will suggest novel approaches to prevention and treatment of alcoholism and related disorders.