Cross-species investigation of gene networks for ethanol-related behaviors

项目概要-总体 酒精使用障碍（AUDs）是一个主要的公共卫生负担。遗传风险因素导致 对AUD的易感性至关重要，并且可能是许多变体的结果，每种变体对风险的贡献都很小。 迄今为止，动物模型和人类的遗传学研究在识别个体方面进展缓慢。 遗传风险变异。然而，全基因组关联研究等现代高通量方法 或基因组表达谱有望迅速增加潜在的候选基因库， AUD。本方案为P50酒精研究中心提出了一种新颖的、高度集成的整体设计方案 重点是基因发现和功能解释的遗传学AUDs。本申请是 更新我们目前资助的P50，支持VCU酒精研究中心（VCU-ARC），这是 2009年首次获得P20发展中心的资助。我们在过去取得了重大进展 4.5多年来，我们在这里寻求继续我们先前方向的各个方面，但也将我们的工作扩展到新的领域。 地区 我们的方法仍然是创新的和重要的，由于三个新的特点：1）对基因的关注 网络有助于AUD相关的表型和乙醇行为，而不是单个基因; 2）交叉- 物种遗传学和基因组学分析，以验证影响乙醇行为的候选基因和网络; 和3）高度集成的中心设计，通过跨物种的跨项目快速共享数据 分析管道，以提供排序的基因列表或网络，用于在组件中进行进一步的实验验证 项目我们要求为五个研究项目提供五年的支持，并为遗传研究提供试点赠款。 蠕虫、苍蝇、老鼠和人类。三个项目将代表新的研究领域，而另外两个项目将 更新当前项目的总体战略，但要有新的研究领域。两个项目将在 人类遗传学与国家的最先进的统计方法，以利用大基因组的力量， 与AUD显著相关的表型的关联和外显子组测序研究。所有项目将 由一个行政核心、一个生物信息学和分析核心以及一个啮齿动物行为核心提供支持。 在这些项目和核心中提出的科学工作显然大于其各部分的总和，因为 VCU-ARC组件的高度交互式结构。VCU-ARC已做好充分准备， 国家资源，作出重大贡献，以促进我们的病因学的理解， AUDs及其预防和治疗。

Project Summary – Overall Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs and are likely a result of many variants each contributing modestly to risk. Genetic studies in animal models and humans have to date made slow progress in identifying individual genetic risk variants. However, modern high-throughput approaches such as genome-wide association studies or genomic expression profiling promise to rapidly increase the pool of potential candidate genes influencing AUDs. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design to focus on both gene discovery and functional interpretation for the genetics of AUDs. This application is a renewal of our currently funded P50 that supports the VCU Alcohol Research Center (VCU-ARC), which was first funded with a P20 Developmental Center grant in 2009. We have made significant progress over the past 4.5 years and here seek to both continue aspects of our prior directions but also to extend our work into new areas. Our approach continues to be innovative and significant due to three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes and ethanol behaviors, rather than single genes; 2) A cross- species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; and 3) A highly integrative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists or networks for further experimental validation in the component projects. We request five years of support for five research projects and pilot grants for genetic studies in worms, flies, mice, rats and humans. Three projects will represent new areas of study, while two others will renew their overall strategy of current projects but with novel areas of investigation. Two projects will be in human genetics with state-of-the-art statistical approaches to leverage the power of large genome-wide association and exome sequencing studies on phenotypes significantly associated with AUDs. All projects will be supported by an Administrative Core, a Bioinformatics and Analysis Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores is clearly greater than the sum of its parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to become a national resource, making major contributions to the advancement of our understanding of the etiology of AUDs and subsequently their prevention and treatment.