Molecular Epidemiology of Alcoholism 2- Big Sibships

描述（由申请人提供）：该IRPG申请寻求对一项研究计划的支持，该研究计划使用从澳大利亚双胞胎登记处及其兄弟姐妹的一般人群调查中确定的流行病学信息样本，对导致重度饮酒和酒精（以及相关烟草）依赖风险变化的基因进行定位。这个IRPG组件，IRPG 2，侧重于查明大型澳大利亚同胞（目标N=360个平均大小为6.7个同胞的同胞）进行400个标记的10 cM基因组扫描，使用应用于大量饮酒的定量指标的多变量方差分量连锁方法，在这个社会中已显示出（i）高遗传性（45- 52%），在整个饮酒水平范围内，这不是遗传性精神病学、社会人口学、体重指数或其他风险因素造成的;（ii）与酒精依赖风险的高度遗传相关性（0.82）以及尼古丁依赖（0.72）;（iii）人群中的连续和近似正态分布;（iv）高重测信度（0.74-0.81重测相关性）。通过对1981年和1989年的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个具有5个或更多全同胞兄弟姐妹（范围5-15）的大兄弟姐妹。目标是筛选其中最大的，排除与死亡或不合作的兄弟姐妹，或与最小的酒精暴露的兄弟姐妹，并获得血液样本，酒精依赖终身史的诊断访谈数据（DSM-IIIR，DSM-IV），吸烟和烟草依赖，相关精神病风险因素（重性抑郁症、焦虑症、儿童期品行障碍病史）和终生最大和最重时期饮酒量的定量指标（目标N=4000）。将使用360个信息量最大的同胞（目标N=2400个个体）完成基因组扫描。将使用方差分量连锁方法（结合IRPG 3）来映射基因，这些基因有助于定量饮酒指数的变化，并共同有助于这些定量指数以及酒精（和一些位点也烟草）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.