IRPG5 R01:NOVEL PHENOTYPES FOR GENETICS OF ALCOHOLISM

印第安纳大学互动研究项目(IU-IRPG)是八个提出的IRPG项目之一，其长期目标是阐明导致酒精中毒(酒精依赖)易感性和严重性的可遗传表型和潜在的遗传机制。为此，将在来自不同种族群体的密集影响和对照家系的队列中研究已建立的和潜在的与酒精中毒相关的表型性状之间的关系，以及它们与候选基因和数量性状基因座(QTL)的关联和连锁。在拟议的研究中，将确定中枢神经系统(CNS)去抑制量化措施的遗传度，并将其与易感性和/或共病的轴I和II精神障碍的临床诊断相关联。被认为是酒精依赖基本因素的中间表型将使用量化量表进行评估，确定它们的遗传度，并分析它们与酒精中毒严重程度的关系。这些表型背后的基因将通过全基因组调查和候选基因关联研究来寻找。IU-IRPG建议确定这些目标所需的遗传信息群体的公平份额，并评估他们的神经去抑制的新表型。此外，我们将使用BRAC钳制程序来定义酒精急性反应的新表型和酒精清除率。我们将估计这些表型以及与饮酒量-频率、耐受性、失控、饮酒欲望和身体戒断有关的量化临床表型的遗传度。最后，我们将提供验证我们的假设所需的一半的基因分型和基因分析，并将为IRPG数据库的部分内容提供数据管理服务。

The Indiana University interactive research program project (IU-IRPG) is one of eight proposed IRPGs whose long-term goal is the elucidation of heritable phenotypes and underlying genetic mechanisms that contribute to alcoholism (alcohol dependence) susceptibility and severity. To this end, the relationships among established and potentially alcoholism-relevant phenotypic traits and their association and linkage to candidate genes and quantitative trait loci (QTLs) will be studied in a cohort of densely affected and control families from ethnically diverse populations. In the proposed studies, the heritability of quantitative measures of central nervous system (CNS) disinhibition will be determined and correlated with clinical diagnoses of predisposing and/or comorbid Axis I and II psychiatric disorders. Intermediate phenotypes considered to be fundamental elements of alcohol dependence will be assessed using quantitative scales, their heritability determined, and their relationship to severity of alcoholism analyzed. The genes that underlie these phenotypes will be sought through a genome wide survey and candidate gene association studies. The IU-IRPG proposes to ascertain a fair share of the genetically informative population necessary for these goals and to assess them for novel phenotypes of neural disinhibition. In addition, we will use the BrAC clamping procedure to define novel phenotypes of the acute response to alcohol and the alcohol elimination rate. We will estimate the heritability of these phenotypes and of the quantitative clinical phenotypes relating to quantity-frequency of drinking, tolerance, loss of control, craving for alcohol, and physical withdrawal. Finally we will contribute half the genotyping and genetic analyses required to test our hypotheses, and will provide data management services for portions of the IRPG database.