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

酒精依赖(AD)是一个主要的公共卫生问题。先前的研究表明，基因 各种因素在AD的发病机制中起着关键作用。该项目的目标是确定特定的易感基因座(SL) 这对AD的风险有影响。这项建议建立在我们正在进行的受爱尔兰影响的兄弟姐妹所取得的成就之上 酒精依赖研究(IASPSAD)和其他VCU-ARC组分的研究。在两个月内 在之前的资助期间，我们1)完成了受影响的大兄弟姐妹对的收集和对照样本 AD在爱尔兰，2)完成并分析了AD、AD症状和其他与酒精有关的基因组扫描 表型(Arp)和3)已经开始测试生理和位置候选基因：我们有 用NIAAA开发的“成瘾阵列”筛选122个基因，完成了我们的439个标记 4号染色体连锁达到顶峰，完成了AD的全基因组联合(GWA)。我们有 为AD和ZNF699之间的关联提供了强有力的证据，ZNF699是果蝇的人类同源物 吉恩·宿醉。 本次P20中心发展项目资助金申请有4个具体目标：i)全面 在1号染色体连锁区域筛选与AD和Arps相关的基因和EST 我们抽取的562例遗传独立病例样本中的初始敏感性和耐受性的证据 每个家庭一个来自同胞对样本和569个对照，使用信息标签单核苷酸 多态(SNPs)；ii)每年在我们的人类样本中评估最多两个选定的和优先考虑的基因座 由来自其他VCU-ARC组分的其他生物(小鼠，线虫， 果蝇)或文献，并类似地贡献相关的人类基因座作为进一步的候选 对VCU-ARC其他组成部分使用的模式生物进行评估；三)使用数据 从这些研究中对基因选择和优先排序方法的性能进行实证评估 由VCU-ARC生物信息学核心开发，并进一步发展选择和 确定优先顺序的方法；四)在二次分析中评估已确认的基因座对其他表型的影响 建议的样本中有哪些数据，包括AD的其他方面，尼古丁依赖，非法 药物依赖、抑郁和品行障碍，以明确表型谱。

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.