NOVEL PHENOTYPES FOR THE GENETIC ANALYSIS OF ALCOHOLISM

这项来自华盛顿大学的建议是一个新的五年，八个中心，调查员发起的互动研究项目（IRPG）的一部分。 该IRPG的总体目标是研究酒精中毒，人格特征和神经去抑制的神经生理学指标与酒精成瘾因素之间的遗传关系，包括耐受性，敏感性，戒断，渴望和失控的定量指标。 作为IRPG联盟的一员，我们将确定和评估为酒精中毒和相关表型的候选基因和遗传连锁遗传学研究提供信息的家庭。 我们还将监督和协调信息家庭的确定，并在所有中心实施质量保证计划。 我们将对所有研究中心的家庭进行基因分型，维护数据管理设施/储存库，并进行连锁和候选基因研究。 我们的数据分析团队的成员将开发和扩展分类和定量表型的分析，包括多位点假设的测试和多表型的分析。 遗传连锁和候选基因研究将在受影响严重的多代酒精依赖先证者家族中进行，这些家族具有种族多样性。 计划分两波进行全基因组调查和候选基因关联研究。这些表型的QTL之间的遗传关系进行了研究，以检验加性，多效性，等位基因异质性和上位性互作的假设。 在高风险和低风险受试者中进行的正电子发射断层扫描（PET）研究将检验酒精依赖中GABA能抑制解除的假设。

This proposal from Washington University is part of a new a new five-year, eight center, Investigator-Initiated Interactive Research Project (IRPG). The overall goal of this IRPG is to study genetic relationships between alcoholism, personality traits and neurophysiological measures of neural disinhibition and elements of addiction to alcohol including quantitative measures of tolerance, sensitivity, withdrawal, craving and loss of control. As a member of the IRPG consortium, we will ascertain and assess families that are informative for candidate gene and genetic linkage genetic studies of alcoholism and related phenotypes. We will also monitor and coordinate the ascertainment of informative families and implement a quality assurance program at all centers. We will genotype families from all sites, maintain a data management facility/repository and conduct linkage and candidate gene studies. Members of our data analysis team will develop and extend the analysis of categorical and quantitative phenotypes to include tests of multilocus hypotheses and the analyses of multiple phenotypes. Genetic linkage and candidate gene studies will be conducted in densely affected, multigenerational families of alcohol dependent probands that are ethnically diverse. A genome wide survey in two waves and candidate gene association studies are planned. The genetic relationships between QTLs for these phenotypes will be studied to test hypotheses of additivity, pleiotropy, allelic heterogeneity and epistatic interaction. A Positron Emission Tomography (PET) study in high and low risk subjects will test GABAergic hypotheses of disinhibition in alcohol dependence.