Molecular Epidemiology of Alcoholism 2- Big Sibships

描述（由申请人提供）：本IRPG申请旨在支持一项研究计划，以定位导致重度饮酒和酒精（及相关烟草）依赖风险变异的基因，使用从澳大利亚双胞胎登记处及其兄弟姐妹的一般人口调查中确定的流行病学信息样本。IRPG组成部分，IRPG2，专注于确定大型澳大利亚兄弟姐妹（目标N=360个兄弟姐妹，平均身高6.7）进行400标记10cM基因组扫描，使用多变量方差成分链接方法应用于大量饮酒的定量指标，在这个社会中已经显示出(i)高遗传性（45-52 %），在整个酒精消费水平范围内，这不是由遗传精神病学，社会人口学，身体质量指数或其他危险因素；（ii）与酒精依赖风险（0.82）和尼古丁依赖风险（0.72）具有高度遗传相关性；（iii）人口中的连续和近似正态分布；（iv）重测信度高（重测相关系数0.74 ~ 0.81）。通过对1981年和1989年澳大利亚双胞胎小组以及1981年小组的配偶的调查，已经确定了1900个拥有5个或更多完整兄弟姐妹（范围5-15）的大兄弟姐妹。目标是筛选其中最大的，排除与已故或不合作的兄弟姐妹，或与酒精接触最少的兄弟姐妹，并获得血液样本，关于终身酒精依赖史（DSM-IIIR, DSM-IV），吸烟和烟草依赖，相关精神风险因素（重度抑郁症，焦虑症，儿童行为障碍史）的诊断访谈数据，终生最大和最重期酒精消费量的定量指标（目标N=4000）。基因组扫描将使用360个信息最丰富的兄弟姐妹（目标N=2400个个体）完成。将使用方差成分连锁方法（与IRPG3一起）来绘制导致定量酒精消费指数变异的基因图谱，这些基因共同影响这些定量指数以及酒精（某些基因座也包括烟草）依赖风险。

DESCRIPTION (provided by applicant): This IRPG application seeks support for a research program to localize genes that contribute to variation in heavy drinking and alcohol (and associated tobacco) dependence risk, using epidemiologically informative samples ascertained from general population surveys of the Australian Twin Registry and their siblings. This IRPG component, IRPG2, focuses on the ascertainment of large Australian sibships (target N=360 sibships of average size 6.7 siblings) for a 400 marker 10cM genome scan, using a multivariate variance components linkage approach applied to quantitative indices of heavy drinking, that have been shown in this society to exhibit (i) high heritability (45-52 percent), throughout the range of alcohol consumption levels, that is not accounted for by inherited psychiatric, sociodemographic, body-mass index or other risk-factors; (ii) high genetic correlation with alcohol dependence risk (0.82) as well as with nicotine dependence (0.72); (iii) a continuous and approximately normal distribution in the population; and (iv) high test-retest reliability (0.74-0.81 retest correlations). 1900 large sibships with 5 or more full siblings (range 5-15) have already been identified through surveys of the Australian twin panel 1981 and 1989 cohorts, and the spouses of the 1981 panel. The goal is to screen the largest of these, excluding sibships with deceased or uncooperative siblings, or with siblings with minimal alcohol exposure, and obtain blood samples, diagnostic interview data on lifetime history of alcohol dependence (DSM-IIIR, DSM-IV), smoking and tobacco dependence, associated psychiatric risk-factors (history of major depression, anxiety disorders, childhood conduct disorder), and quantitative indices of lifetime maximum and heaviest period alcohol consumption (target N=4000). A genome scan will be completed using the 360 most informative sibships (target N=2400 individuals). Variance components linkage methods will be used (in conjunction with IRPG3) to map genes that contribute to variation in the quantitative alcohol consumption indices and that contribute jointly to these quantitative indices as well as to alcohol (and for some loci also tobacco) dependence risk.