Center for Genetic Studies of Drug Abuse in Outbred Rats

项目总结(总体) 申请续期的目的是继续我们中心的成功活动，该中心使用 应用定量遗传技术研究近交系大鼠药物滥用相关行为的遗传基础。 当我们的中心在2014年6月最初获得资金时，我们的目标是发展远缘杂交的N/NIH异种 股票(HS)大鼠作为一个平台，对难以或不可能在小鼠身上研究的行为进行遗传研究。 最初的四年资金使我们能够利用HS大鼠建立一个充满活力的调查社区 研究药物滥用和其他特征，我们称之为生态系统。这个生态系统既包括 直接参与此次续签申请的调查人员以及其他许多已获得 单独的资金，一些来自NIDA，一些来自其他来源。这一生态系统的增长反映了 我们中心作为国家资源的方式。我们正在提出三个项目，涉及 HS大鼠的各种特征的表型，包括静脉注射可卡因和尼古丁自我给药， 对新奇事物、社交行为、反应时间和延迟折扣的反应。其中两个项目是 从上一个资助期延续，旨在将我们的样本量从1,600增加到3,200 每种表型的大鼠。我们提供的数据表明，这样的增长会产生指数级的增长 重大发现的数量。这种方法与SUD的人类遗传学研究平行，后者还 从更大的样本量中受益匪浅。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，我们还将测量基因在行为方面的表达 幼稚的大鼠使用RNAseq，并使用这些数据来识别表达数量性状基因座(EQTL)。到时候我们会的 整合GWAS和eQTL数据，努力识别影响行为表型的特定基因。 许多正在研究的行为领域都是已知的性二态；我们的研究将同时使用这两种方法 雄鼠和雌鼠，这将使我们能够通过基因相互作用来识别性别差异和性别。我们会 也研究遗传相关性，进行表型范围的关联研究(Phewas)，转录组范围 并探索一种称为多基因转录风险评分(PTRS)的新策略， 这是为了允许跨物种的多基因信号的翻译。项目4将使用基于网络的 将我们的GWAS扩展到考虑已知的生物网络的方法。这项拟议的续期还包括 支持新方向和利用不可预见的机会的试点项目核心。最后我们 建议建立一个行政核心，以支持中心的许多活动，包括教育、职业 发展和公众宣传。这些研究的结果将加深我们对 基因在一系列复杂的心理行为中，并将提供新的生物学见解，可能 支持今后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.