COLLABORATIVE STUDY ON THE GENETICS OF ALCOHOLISM/COGA

酒精中毒是一种复杂的疾病，受遗传易感性、环境因素和 基因之间以及基因与环境之间的相互作用。该提案是为了将 酒精中毒遗传学合作研究（COGA），一个八个地点的国家合作， 确定和表征影响酒精易感性的基因的总体目标 依赖和相关表型。这种更新是基于这样一种假设，即某些基因 受影响的易感性差异是酒精中毒所独有的，而其他人，涉及额叶功能， （冲动，神经去抑制）影响一系列相关的结果，包括外化和情绪 其他物质的滥用和滥用。 COGA已经确定了几个影响酒精中毒发展的基因及其相关基因。 表型，包括反映基本神经机制的内表型。我们建议， 联合收割机结合神经生理学和临床/行为表型的发展的成功策略 通过广泛的SNP基因分型和连锁不平衡分析， 表型，并检查其影响表型的机制。基因功能研究 与重要表型密切相关，包括检查潜在的编码和剪接 将进行启动子功能的差异和潜在差异。青少年前瞻性研究 和年轻的成年人也提出了新的神经生理和其他表型将被测量 并接受基因分析。这将有助于进一步了解特定基因的作用以及如何 它们相互作用并与环境相互作用，影响着 酒精中毒和相关表型。这些组成部分是相互关联的，都有助于主题 识别和理解影响酒精中毒和相关表型的遗传和环境因素， 期望这些知识将为预防和治疗 酒精中毒和相关疾病。

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 its 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 phenotypes 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.