IRPG4:NOVEL PHENOTYPES FOR GENETICS OF ALCOHOLISM

酗酒影响了非裔美国人的社会、环境和医疗结果，带来了毁灭性的经济后果。霍华德大学互动研究计划(Howard-IRPG)提出的这项研究的总体目标是增加对非裔美国人酗酒和酗酒风险的遗传易感性的了解。这项研究基于一个概念模型，即基因影响在酒精中毒所必需的三个条件中的每一个中都是明显的：行为去抑制、大量饮酒的能力和身体依赖的发展。行为去抑制可能与酒精中毒风险增加有关，神经去抑制可能是行为的基础。Howard-IRPG是建议的八个IRPG位点之一，其长期目标是阐明与酒精中毒易感性和严重性有关的新的可遗传表型。使用IRPG确定标准，我们计划对50个受影响密集的城市非裔美国家庭和20个对照家庭进行识别、筛选、招募、以及进行确定和评估研究。这些研究将量化特定诊断标准所定义的酒精滥用和依赖高风险的表型，估计特定表型性状的遗传力，并确定它们与候选基因和数量性状基因座(QTL)的关联和联系。这些评估将包括神经去抑制的数量表型的遗传性，以及与易患和/或共病的I型和II型轴疾病的临床诊断的相关性。BRAC钳制程序将用于确定酒精急性反应的新表型和酒精清除率。我们将为验证这些假设所需的全基因组调查分析、候选基因关联研究和基因多态测定贡献一大批非裔美国人，因为非裔美国人在乙醇代谢方面可能存在显著的、由基因决定的差异。此外，Howard IRPG结合了许多招聘地点的可用性和现有的科学和行政团队，以应对招募大量信息丰富的非裔美国家庭的挑战；在类似测试仪器和程序的管理方面提供丰富的现有培训/经验，如SSAGA和BRAC夹紧技术；可用NIH资助的新的GCRC，能够支持BRAC夹紧共享资源；以及NIAAA合作少数族裔酒精研究中心的现有行政和科学基础设施。这些研究将通过与所有拟议的IRPG成员网站进行重大互动来完成。

Alcoholism affects social, environmental and medical outcomes in African Americans with devastating economic consequences. The overall goal of the research proposed by the Howard University Interactive Research Program (Howard-IRPG) is to increase understanding of the genetic susceptibility to alcoholism and alcoholism risk among African Americans. The research is based on the conceptual model that genetic influence is manifest in each of three conditions necessary for alcoholism: behavioral disinhibition, the capacity to consume large quantities of alcohol, and the development of physical dependence. Behavioral disinhibition may be associated with increased risk for alcoholism and neural disinhibition may underlie the behavior. The Howard-IRPG is one of eight proposed IRPG sites whose long- term goal is the elucidation of novel heritable phenotypes that contribute to alcoholism susceptibility and severity. Using the IRPG ascertainment criteria, we plan to identify, screen, recruit, and perform ascertainment and assessment studies on a cohort of 50 densely affected urban African American families and 20 control families. These studies will quantify phenotypes of high risk of alcohol abuse and dependence as defined by specific diagnostic criteria, estimate the heritability of specific phenotypic traits and determine their association and linkage to candidate genes and quantitative trait loci (QTLs). These assessments will include the heritability of quantitative phenotypes of neural disinhibition and the correlation with clinical diagnoses of predisposing and/or co-morbid Axis I and II disorders. The BrAC clamping procedure will be used to define novel phenotypes of the acute response to alcohol and the alcohol elimination rate. We will contribute a significant cohort of African Americans for a genome wide survey analysis, candidate gene association studies and the determination of genetic polymorphism required to test these hypotheses since African Americans may have significant, genetically-determined differences in ethanol metabolism. In addition, The Howard IRPG combines the availability of many recruitment sites and an existing scientific and administrative team to meet the challenge of recruiting large numbers of informative African American families; offers substantial existing training/experience in the administration of similar test instruments and procedures such as the SSAGA and the BrAC clamping technique; availability of a new, NIH-funded GCRC with the ability to support the BrAC clamping Shared Resource; and the existing administrative and scientific infrastructure of a NIAAA Collaborative Minority Alcohol Research Center. These studies will be accomplished through significant interaction with all of the proposed IRPG member sites.