Molecular Epidemiology of Alcoholism 2- Big Sibships

描述(由申请人提供)：此IRPG申请寻求支持一项研究计划，利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，定位导致大量饮酒和酒精(及相关烟草)依赖风险变异的基因。IRPG组件IRPG2集中于确定400标记10 cM基因组扫描的澳大利亚大型兄弟姐妹(目标N=360个兄弟姐妹，平均大小6.7个兄弟姐妹)，使用应用于大量饮酒的定量指标的多变量方差分量链接方法，该社会已显示出：(I)在整个饮酒水平范围内，未被遗传的精神、社会人口、体重指数或其他风险因素解释的高遗传率(45%-52%)；(Ii)与酒精依赖风险(0.82)以及尼古丁依赖(0.72)的高度遗传相关性；(Iii)总体呈连续且近似正态分布；及(Iv)高重测信度(0.74-0.81重测相关)。通过对1981年澳大利亚双胞胎小组和小组的队列以及1981年小组的配偶的调查，已经确定了1900个有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一个，不包括兄弟姐妹中已故或不合作的兄弟姐妹，或兄弟姐妹中酒精暴露最少的兄弟姐妹，并获得血液样本、关于终生酒精依赖史(DSM-IIIR、DSM-IV)、吸烟和烟草依赖的诊断性访谈数据、相关的精神危险因素(严重抑郁症、焦虑症、儿童品行障碍病史)以及一生最大和最重度饮酒的量化指标(目标N=4000)。将使用360个信息量最大的兄弟姐妹(目标N=2400人)完成基因组扫描。将使用方差分量连锁方法(与IRPG3一起)来定位导致定量酒精消费指数变化的基因，以及共同影响这些定量指数以及酒精(对于某些基因座还包括烟草)依赖风险的基因。

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.