Center for Genetic Studies of Drug Abuse in Outbred Rats

项目摘要/摘要(项目3) 该项目的主要目标是在动物模型中找到个体差异的遗传变异。 通常与药物滥用有关的心理特征，包括感觉寻求，社交方式，注意力不集中， 和冲动。在目前的资助期(3个月前开始的第5年)，我们几乎达到了以下目标 1600只异种大鼠(HS)的表型。我们已经估计了所有行为的SNP遗传率 特征，并确认它们在适合全基因组关联的范围内；事实上，它们 是该中心研究的所有行为中观察到的最高水平之一。通过使用遗传相关性，我们有 我们的测量结果与项目2中研究的结果之间估计的共同遗传影响(社会习得 尼古丁自我给药)。虽然我们的研究仍在进行中，但我们已经在全基因组范围内确定了许多 重要的联系。与我们的表型相关的几个数量性状基因座(QTL)仅包含 一些基因。这一极其准确的地图是HS人口的一个关键特征，将有助于 确定每个基因座内的致病基因。在某些情况下，候选基因列表可以进一步 通过重叠的基因表达QTL缩小了范围。人类的GWA和我们最近完成的 几个生理性状(n~3,200)表明，增加样本量会导致指数 全基因组显著点击率的增加。基于我们的表型鉴定流水线在前一年取得的成功 在资助期内，我们建议在这五只上额外表型1600只雄性和雌性HS大鼠 行为任务。我们的研究安排如下：在目标1，我们将对1600只HS大鼠进行表型 由核心B(HS繁育核心)提供所有五种行为测试。每年我们将研究400只大鼠(2亿只和 200华氏度)。将使用现有的方案进行表型鉴定，这样整个3200只大鼠的数据集就可以 一起分析。在目标2中，我们将分析大量的行为数据(每只大鼠超过100个测量) 并让他们为GWA做好准备。在对这些数据进行严格的质量检查后，我们将把它们提交给Core A (管理核心)录入数据库，然后由核心C用于GWAS(基因分型， RNA-Seq和GWAs)。在目标3中，我们将进行遗传关联、表型关联和元分析。 利用从不同动物群中获得的特征进行分析。我们处于一个独特的位置，能够 研究冲动的三种行为模式之间的共同和独特的遗传影响。我们还将使用 这些方法来检查我们研究的心理特征和药物之间的共同遗传因素- 相关性状由项目1(可卡因)、项目2(尼古丁)和其他附属U01(可卡因、羟考酮)研究。

Project summary/Abstract (Project 3) The primary goal of the project is to find genetic variants underlying the individual differences in animal models of psychological traits often related to drug abuse, including sensation seeking, social approach, inattention, and impulsivity. In the current funding period (Year 5 began 3 months ago) we have almost reached our goal of phenotyping 1,600 heterogenous stock (HS) rats. We have estimated the SNP heritability of all the behavioral traits and confirmed that they are within a range suitable for genome-wide association (GWAS); indeed they are among the highest observed for any behavior studied by this center. By using genetic correlation, we have estimated shared genetic influences between our measures and those studied in Project 2 (Socially acquired nicotine self-administration). While our study is still ongoing, we have already identified many genome-wide significant associations. Several of the quantitative trait loci (QTL) associated with our phenotypes contain only a few genes. This extremely accurate mapping is a key feature of the HS population and will facilitate identification of the causal gene within each locus. In some cases, the list of candidate genes can be further narrowed by an overlapping gene expression QTL. Both human GWAS and our recently completed GWAS of several physiological traits (n~3,200) have shown that increasing sample size results in an exponential increase in genome-wide significant hits. Based on the success of our phenotyping pipeline during the previous funding period, we are proposing to phenotype an additional 1,600 male and female HS rats on these five behavioral tasks. Our proposed studies are arranged as follows: In Aim 1. we will phenotype 1,600 HS rats provided by Core B (HS breeding core) on all five behavior tests. Each year we will study 400 rats (200M and 200F). Phenotyping will be conducted using existing protocols so that the entire dataset of 3,200 rats can be analyzed together. In Aim 2, we will analyze the vast amount of behavior data (over 100 measures per rat) and prepare them for GWAS. After rigorous quality checking of these data, we will submit them to Core A (Administrative Core) to be entered into a database and subsequently used for GWAS by Core C (genotyping, RNA-Seq, and GWAS). In Aim 3, we will conduct genetic correlation, phenome-wide association, and meta- analysis using traits obtained from different cohort of animals. We are in an unique position of being able to study the shared and unique genetic influences between three behavior models of impulsivity. We will also use these methods to examine the shared genetic factors between the psychological traits we study and the drug- related traits studied by Project 1 (cocaine), Project 2 (nicotine) and other affiliated U01s (cocaine, oxycodone).