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补充支持，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IRPG的重点是查明大型澳大利亚同胞（目标N=360个平均大小为6.7个兄弟姐妹的同胞）进行0.5cM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，在该社会中已经显示出（i）在整个酒精消费水平范围内的高遗传性（45-52%），这是不占遗传精神，社会人口，身体质量指数或其他风险因素;（ii）高遗传相关性与酒精依赖风险（0.82）以及尼古丁依赖（0.72）;（iii）在总体中的连续和近似正态分布;（iv）高的重测信度（0.74-0.81重测相关）。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。目前，已收集了300多个家庭的基因组DNA样本和关于酒精依赖（DSM-IIIR，DSM-IV）、吸烟和烟草依赖、相关精神病风险因素（重度抑郁症、焦虑症、儿童行为障碍史）以及一生最大和最重时期酒精消费的定量指数的诊断访谈数据。本补充申请要求资金，以完成单核苷酸多态性（snp）为基础的基因组扫描使用最翔实的同胞（目标N=1800人）。方差分量连锁方法将被用来映射基因，有助于变化的定量酒精消费指数，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。参与酒精中毒发展和过程的新基因的发现可能会对酒精中毒新药物治疗的发展产生深远的影响，并为识别风险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.