IRPG2, R01, NOVEL PHENOTYPES FOR THE GENETIC ANALYSIS

这项来自华盛顿大学的提案是一个新的为期五年，为期八个中心的研究人员发起的互动研究项目（IRPG）的一部分。本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测量以及酒精成瘾因素之间的遗传关系，包括耐受性、敏感性、戒断、渴望和失去控制的定量测量。作为IRPG联盟的一员，我们将确定和评估家庭，为候选基因和遗传连锁的酒精中毒和相关表型遗传研究提供信息。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。我们将对所有站点的家族进行基因分型，维护数据管理设施/存储库，并进行连锁和候选基因研究。我们的数据分析团队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种表型的分析。遗传联系和候选基因研究将在种族多样化的酒精依赖先证者的多代家庭中进行。计划进行两波基因组调查和候选基因关联研究。将研究这些表型的qtl之间的遗传关系，以检验加性、多效性、等位基因异质性和上位互作的假设。一项针对高风险和低风险受试者的正电子发射断层扫描（PET）研究将检验gaba能对酒精依赖解除抑制的假设。

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.