Molecular Epidemiology of Alcoholism 2-Big Sibships

描述（由申请人提供）：本IRPG申请旨在为一项研究项目寻求补充支持，该项目旨在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群调查中确定的流行病学信息样本。该IRPG的重点是通过0.5 cM基因组扫描确定大型澳大利亚兄弟姐妹（目标N=360个平均体格为6.7的兄弟姐妹），使用应用于大量饮酒定量指标的多变量方差成分连锁方法，在该社会中显示出(i)在整个酒精消费水平范围内具有高遗传性（45-52%），不受遗传性精神病学、社会人口学、体重指数或其他风险因素的影响；（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。目前，已经收集了300多个家庭的终生酒精依赖史（DSM-IIIR、DSM-IV）、吸烟和烟草依赖、相关精神危险因素（重度抑郁症、焦虑症、儿童行为障碍史）以及终生最大和最重期酒精消费定量指标的基因组DMA样本和诊断访谈数据。这个补充申请要求资金来完成基于单核苷酸多态性（snp）的基因组扫描，使用最具信息量的兄弟姐妹（目标N=1800个个体）。方差成分连锁方法将用于绘制导致定量酒精消费指数变异的基因，以及共同影响这些定量指数以及酒精（某些基因座也包括烟草）依赖风险的基因。参与酒精中毒发展和过程的新基因的发现可能对酒精中毒的新药理学治疗的发展产生深远的影响，并为识别高危个体和研究饮酒问题发展中的基因-环境相互作用提供生物标志物。

DESCRIPTION (provided by applicant): This IRPG application seeks supplemental 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 focuses on the ascertainment of large Australian sibships (target N=360 sibships of average size 6.7 siblings) for a 0.5 cM 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%), 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. Currently, genomic DMA samples and 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 have been collected on over 300 families. This supplemental application requests funds to complete a single nucleotide polymorphism (snp) based genome scan using the most informative sibships (target N=1800 individuals). Variance components linkage methods will be used 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. The discovery of new genes involved in the development and course of alcoholism could have a profound impact on the development of novel pharmacological treatments for alcoholism as well as provide biomarkers for the identification of at risk individuals and the study of gene-environment interactions in the development of drinking problems.