Center for Genetic Studies of Drug Abuse in Outbred Rats

项目概要（总体） 此续订申请的目的是继续我们中心的成功活动，该中心使用 定量遗传技术研究远交大鼠药物滥用相关行为的遗传基础。 当我们的中心最初于 2014 年 6 月获得资助时，我们的目标是开发近交 N/NIH 异种 股票（HS）大鼠作为对小鼠难以或不可能研究的行为进行遗传研究的平台。 前四年的资金使我们能够利用 HS 大鼠建立一个充满活力的研究人员社区 研究药物滥用和其他特征，我们称之为生态系统。这个生态系统包括 直接参与本次续展申请的调查人员以及许多其他已获得 单独的资金，一些来自 NIDA，一些来自其他来源。这个生态系统的增长反映了以下之一 我们中心作为国家资源的方式。我们提出了三个项目，涉及 对 HS 大鼠的多种特征进行表型分析，包括静脉注射可卡因和尼古丁自我给药， 对新奇事物的反应、社交行为、反应时间和延迟折扣。其中两个项目是 上一个资助期的延续，旨在将我们的样本量从 1,600 增加到 3,200 每个表型的大鼠。我们提供的数据表明，这种增加会导致 重要发现的数量。这种方法与 SUD 的人类遗传学研究相似，后者也 更大的样本量使我们受益匪浅。我们将利用这些数据进行全基因组关联 研究（GWAS）和一套相关技术。此外，我们还将测量行为方面的基因表达 使用 RNASeq 的幼稚大鼠并使用这些数据来识别表达数量性状基因座 (eQTL)。我们随后将 整合 GWAS 和 eQTL 数据，以识别影响行为表型的特定基因。 众所周知，正在研究的许多行为领域都具有性别二态性。我们的研究将同时使用 雄性和雌性大鼠，这将使我们能够通过基因型相互作用来识别性别差异和性别。我们会 还研究遗传相关性、进行全表型关联研究 (PheWAS)、全转录组研究 关联研究（TWAS）并探索一种称为多基因转录组风险评分（PTRS）的新策略， 其目的是允许跨物种的多基因信号翻译。项目4将使用基于网络的 扩展我们的 GWAS 以解释已知的生物网络的方法。此次拟议的更新还包括 试点项目核心支持新方向并利用不可预见的机会。最后我们 提出一个支持中心许多活动的行政核心，包括教育、职业 发展和公共宣传。这些研究的结果将加深我们对 一系列心理复杂行为中的基因，并将提供新颖的生物学见解 支持未来预防或治疗药物滥用的努力。

Project Summary (Overall) The purpose of this renewal application is to continue the successful activities of our center, which uses quantitative genetic techniques to study the genetic basis of drug abuse-related behaviors in outbred rats. When our center was initially funded in June 2014, our goal was to develop outbred N/NIH heterogeneous stock (HS) rats as a platform for genetic studies of behaviors that were difficult or impossible to study in mice. The first four years of funding have allowed us to establish a vibrant community of investigators using HS rats to study drug abuse and other traits, which we refer to as an ecosystem. This ecosystem includes both the investigators who are directly involved in this renewal application and many others who have obtained separate funding, some from NIDA, and some from other sources. The growth of this ecosystem reflects one of the ways that our center has served as national resource. We are proposing three projects that involved phenotyping HS rats for a variety of traits, including intravenous cocaine and nicotine self-administration, response to novelty, social behavior, reaction time, and delay discounting. Two of those projects are continuations from the prior funding period and are designed to increase our sample size from 1,600 to 3,200 rats per phenotype. We present data showing that such an increase produces an exponential increase in the number of significant findings. This approach parallels human genetics studies of SUD, which have also benefited tremendously from larger sample sizes. We will use these data to conduct genome-wide association studies (GWAS) and a suite of related techniques. In addition, we will measure gene expression in behaviorally naïve rats using RNASeq and use those data to identify expression quantitative trait loci (eQTLs). We will then integrate GWAS and eQTL data in an effort to identify specific genes that influence the behavioral phenotypes. Many of the behavioral domains being studied are known to be sexually dimorphic; our study will use both male and female rats, which will allow us to identify sex differences and sex by genotype interactions. We will also study genetic correlations, perform phenome-wide association studies (PheWAS), transcriptome wide association studies (TWAS) and explore a novel strategy called polygenic transcriptomic risk scores (PTRS), that is intended to allow translation of polygenic signals across species. Project 4 will use a network-based approach to extend our GWAS to account for known biological networks. This proposed renewal also includes a pilot project core to support new directions and take advantage of unforeseen opportunities. Finally we propose an administrative core that supports many activities of the center, including educational, career development and public outreach. The results of these studies will enhance our understanding of the role of genes in a range of psychologically complex behaviors and will provide novel biological insights that may support future efforts at preventing or treating drug abuse.