Molecular Epidemiology of Alcoholism 1--Candidate Gene

该IRPG应用旨在定位对酒精依赖和危险酒精消费易感性变异有重大贡献的基因。我们将首先关注通过对代谢和中毒敏感性的影响来预测影响依赖和消费的基因，使用有酒精依赖史的双胞胎、他们的同卵双胞胎和对照对的DNA。我们还将测试在COGA和其他基因组扫描中确定的候选区域中的位点。在过去的20年里，我们收集了大量关于7000对澳大利亚成年双胞胎及其亲属的饮酒习惯和问题的纵向数据。大约12000对双胞胎和3700对双胞胎的配偶通过结构化的诊断访谈进行了评估。对于3,300人的子样本，我们已经有了DNA样本和选定的遗传标记数据，对于另一个412人（206对）的子样本，我们有了酒精代谢和反应性的详细数据。我们将扩展这一资源，并进行新的分析，以阐明从基因型，通过行为和生化干预表型，到酒精依赖的途径。该应用程序强调在候选区域与紧密间隔的遗传标记的精细作图，并通过连锁不平衡作图在家族内定位基因。我们将获得以下血样：(a)来自910个独立家庭的约1000例AD病例和1000例无关对照——用于常规病例对照分析；(b) AD病例的可用父母，产生至少751组用于传播不平衡测试（TDT）；(c)额外的信息丰富的兄弟姐妹，产生了73个家庭，其中两个AD兄弟姐妹加上父母双方（总共约3800个样本）。相关应用程序计划使用EDAC兄弟姐妹对设计（IRPG3, Heath）和来自澳大利亚双胞胎队列（IRPG2, Todorov）的较大兄弟姐妹对qtl进行10cM连锁扫描，并将为该组件提供其他受影响的兄弟姐妹。该应用程序的优点是：(i)大样本提供了检测小影响的能力；（ii）已经收集了受试者酒精表型的多个方面的纵向数据，允许进行强大的多变量联系和关联分析；（iii）我们以社区为基础的样本提供了人口流行病学视角，但仍然包含大量符合DSM-IV酒精依赖标准的受试者。

This IRPG application aims to locate genes with substantial contributions to variation in susceptibility to alcohol dependence and hazardous alcohol consumption. We shall focus initially on genes predicted to influence dependence and consumption through their effects on metabolism and sensitivity to intoxication, using DNA from twins who have a history of alcohol dependence, their co-twins, and control pairs. We shall also test loci in candidate regions identified in COGA and other genome scans. For the past 20 years we have gathered extensive longitudinal data on the drinking habits and problems of 7,000 pairs of Australian adult twins and their relatives. Some 12,000 twins and 3,700 spouses of twins have been assessed using structured diagnostic interviews. For a sub-sample of 3,300 individuals we already have DNA samples and selected genetic marker data, and for another sub-sample of 412 subjects (206 pairs) we have detailed data on alcohol metabolism and reactivity. We shall extend this resource and perform new analyses to elucidate the pathways from genotype, via behavioral and biochemical intervening phenotypes, to alcohol dependence. This application emphasizes fine mapping with closely spaced genetic markers in candidate areas, and location of genes through linkage disequilibrium mapping within families. We shall obtain blood samples from: (a) approximately 1000 AD cases from 910 independent families, and 1000 unrelated controls - for conventional case-control analysis; (b) available parents of AD cases, generating at least 751 trios for transmission disequilibrium testing (TDT); (c) additional informative siblings, generating 73 families of two AD siblings plus both parents (approximately 3800 samples total). Related applications plan a 10cM linkage scan for QTLs using the EDAC sib-pair design (IRPG3, Heath) and larger sibships from the Australian twin cohorts (IRPG2, Todorov) and will provide additional affected siblings for this component. Strengths of this application are: (i) large samples give power to detect small effects; (ii) longitudinal data have already been gathered on multiple aspects of the alcoholic phenotype of the subjects, permitting powerful multivariate linkage and association analyses; (iii) our community based sample gives a population epidemiologic perspective but nevertheless contains substantial numbers of subjects meeting DSM-IV alcohol dependence criteria.