Project 2: Cross Species Characterization of Gene Networks in Acute Responses

酒精依赖（Alcohol Dependence，AD）是一个严重的公共卫生问题。先前的研究表明， 因素在AD中起着关键的病因学作用。本项目的目标是确定特定的易感基因座（SL） 影响AD的风险。这项建议建立在我们正在进行的爱尔兰受影响同胞对的成就之上 酒精依赖研究（IASPSAD）和其他VCU-ARC组成组的研究。在两 在以前的资助期间，我们1）完成了一个大的受影响的兄弟姐妹对和控制样本的收集， 在爱尔兰的AD，2）完成并分析了AD，AD症状和其他酒精相关的基因组扫描 表型（ARPs）和3）已经开始测试生理和位置候选基因：我们有 利用NIAAA开发的“成瘾阵列”筛选了122个基因，完成了439个标记， 4号染色体连锁峰，完成了AD的合并全基因组关联（GWA）。我们有 为AD和ZNF 699（果蝇的人类同源物）之间的关联提供了强有力的证据 基因宿醉 P20中心发展项目补助金的申请有4个具体目标：i）全面 在显示连锁的1号染色体区域中筛选与AD和ARPs相关的基因和EST 在我们的562例遗传独立病例的样本中， 一个来自同胞对样本的家庭和569个对照，使用信息标记单核苷酸 多态性（SNP）; ii）每年在我们的人类样本中评估多达两个选定和优先的基因座 在来自其他VCU-ARC组分组的其他生物体中的工作表明（小鼠，c.优雅， 果蝇）或文献中，并且类似地贡献相关的人类基因座作为进一步研究的候选者。 其他VCU-ARC组件组使用的模型生物的评估; iii）使用数据 从这些研究中经验性地评估基因选择和优先化方法的性能 由VCU-ARC生物信息学核心开发，并进一步发展选择和 优先排序方法; iv）在二次分析中评估验证的基因座对其他表型的影响 在拟议样本中可获得的数据，包括AD的其他方面、尼古丁依赖、非法 药物依赖、抑郁症和品行障碍，以澄清表型谱。

Alcohol Dependence (AD) is a major public health problem. Prior research demonstrates that genetic factors play a critical etiologic role in AD. The goal of this project is to identify specific susceptibility loci (SL) which impact on risk for AD. This proposal builds on the achievements of our ongoing Irish Affected Sib-Pair Study of Alcohol Dependence (IASPSAD) and those of other VCU-ARC component groups. During two previous funding periods, we 1) completed collections of a large affected sibling pair and control samples for AD in Ireland, 2) completed and analyzed a genome scan for AD, AD symptoms and other alcohol-related phenotypes (ARPs) and 3) have begun to test physiological and positional candidate genes: we have screened 122 genes using the NIAAA developed "addictions array," completed 439 markers under our chromosome 4 linkage peak and completed a pooled genome wide association (GWA) for AD. We have produced strong evidence for association between AD and ZNF699 a human homolog of the Drosophila gene hangover. This application for a P20 Center Developmental Project grant has 4 specific aims: i) to comprehensively screen genes and ESTs for association with AD and ARPs in a region of chromosome 1 showing linkage evidence to both initial sensitivity and tolerance in our sample of 562 genetically independent cases drawn one per family from the sib-pair sample and 569 controls, using information-tagging single nucleotide polymorphisms (SNPs); ii) to assess in our human sample up to two selected and prioritized loci per year suggested by work in other organisms from other VCU-ARC component groups (mouse, c. elegans, drosophila) or the literature, and to similarly contribute associated human loci as candidates for further assessment in the model organisms in use by the other VCU-ARC component groups; iii) to use the data from these studies to empirically assess the performance of the gene selection and prioritization approaches developed by the VCU-ARC Bioinformatics Core, and to further develop the capacities of the selection and prioritization approach; iv) to assess, in secondary analyses, the effects of validated loci on other phenotypes for which data is available in the proposed sample, including other aspects of AD, nicotine dependence, illicit drug dependence, depression and conduct disorder, in order to clarify the phenotypic spectrum.