Center for Genetic Studies of Drug Abuse in Outbred Rats

项目概要（总体） 此更新申请的目的是继续我们中心的成功活动， 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。 当我们的中心最初在2014年6月获得资助时，我们的目标是开发远交的N/NIH异质 因此，研究人员将HS大鼠作为一个平台，用于对难以或不可能在小鼠中研究的行为进行遗传研究。 前四年的资金使我们能够建立一个充满活力的社区调查使用HS大鼠 来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 直接参与这一更新申请的调查人员和许多其他获得 资金来源，一部分来自NIDA，另一部分来自其他来源。这个生态系统的发展反映了 我们中心作为国家资源的方式我们提出了三个项目， 对HS大鼠的各种性状进行表型分析，包括静脉内可卡因和尼古丁自我给药， 对新奇事物的反应，社会行为，反应时间和延迟折扣。其中两个项目是 从上一个融资期延续，旨在将我们的样本量从1，600增加到3，200 大鼠/表型。我们目前的数据表明，这种增加产生指数增加， 一些重大发现。这种方法与SUD的人类遗传学研究平行， 受益于更大的样本量。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，我们将测量基因表达的行为， 使用RNASeq对未处理大鼠进行基因组测序，并使用这些数据来鉴定表达数量性状基因座（eQTL）。然后我们将 整合GWAS和eQTL数据，以确定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性;我们的研究将使用两者 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。我们将 还研究遗传相关性，进行全表型关联研究（PheWAS），全转录组 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， 其旨在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 方法来扩展我们的GWAS，以解释已知的生物网络。此次更新还包括 一个试点项目核心，以支持新的方向，并利用不可预见的机会。最后我们 提出一个行政核心，支持中心的许多活动，包括教育，职业 发展和公共宣传。这些研究的结果将加强我们对 基因在一系列心理复杂的行为，并将提供新的生物学见解， 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.