Center for Genetic Studies of Drug Abuse in Outbred Rats

项目概要/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内（第五年开始于3个月前），我们几乎达到了我们的目标， 表型分型1，600只异种原种（HS）大鼠。我们已经估计了所有行为的SNP遗传率， 他们认为，他们是在一个适合全基因组关联（GWAS）的范围内;事实上，他们 是该中心研究的所有行为中最高的。通过使用遗传相关性，我们有 估计我们的措施和项目2（社会获得性）中研究的措施之间共享的遗传影响 尼古丁自我给药）。虽然我们的研究仍在进行中，但我们已经确定了许多基因组范围内的 重要的协会。与我们的表型相关的几个数量性状基因座（QTL）只包含 一些基因。这种极其精确的绘图是HS人群的一个关键特征， 确定每个基因座内的致病基因。在一些情况下，候选基因的列表可以进一步被确定。 通过重叠的基因表达QTL缩小。人类的GWAS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 增加全基因组的显著命中。基于我们在前一阶段表型分析管道的成功， 在资助期内，我们建议在这五只大鼠上再培养1，600只雄性和雌性HS大鼠 行为任务我们提出的研究安排如下：在目标1。我们将对1,600只HS大鼠进行表型分析 由核心B（HS育种核心）在所有五项行为测试中提供。每年我们将研究400只大鼠（200 M和200 M）， 200 F）。将使用现有方案进行表型分型，以便可以对3，200只大鼠的整个数据集进行分析。 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次测量） 为GWAS做准备在对这些数据进行严格的质量检查后，我们将提交给核心A （管理核心）输入数据库，随后由核心C用于GWAS（基因分型， RNA-Seq和GWAS）。在目标3中，我们将进行遗传相关性，全表型关联和Meta分析。 使用从不同动物群获得的性状进行分析。我们处于一个独特的位置， 研究三种冲动性行为模式之间共有的和独特的遗传影响。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共有的遗传因素， 项目1（可卡因）、项目2（尼古丁）和其他附属U 01（可卡因、羟考酮）研究的相关性状。

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).