COLLABORATIVE STUDY ON THE GENETICS OF ALCOHOLISM/COGA

描述(申请人提供)：酒精中毒是一种复杂的疾病，受到遗传易感性、环境因素以及基因之间和基因与环境之间相互作用的影响。这项提议是对酒精中毒遗传学合作研究(COGA)进行为期五年的续展，这是一个由八个地点组成的国家合作项目，其首要目标是识别和表征影响酒精依赖易感性和相关表型的基因。这种更新是基于这样一种假设，即一些受遗传影响的易感性差异是酒精中毒所特有的，而其他涉及额叶功能(冲动、神经去抑制)的差异会影响一系列相关的结果，包括外化和情绪障碍以及其他物质的滥用。 COGA已经确定了几个影响酒精中毒发展的基因及其相关的表型，包括反映基本神经机制的内表型。我们建议在我们的成功策略的基础上，将神经生理和临床/行为表型的发展与广泛的SNP基因分型和连锁不平衡分析相结合，以确定这些表型的潜在基因，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。还提出了一项针对青少年和年轻人的前瞻性研究，在该研究中，将测量新的神经生理和其他表型，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，以及如何与环境相互作用，以影响酒精中毒和相关表型的发展过程。这些组成部分是相互关联的，所有这些都有助于确定和了解影响酒精中毒和相关表型的遗传和环境因素，期望这一知识将为预防和治疗酒精中毒和相关疾病提出新的方法。

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.