Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits.
Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits.
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DOI：
10.3389/fgene.2022.1003074
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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常见的遗传因素可能导致多种精神疾病，包括情绪和物质使用障碍。某些反映气质的稳定的、可遗传的特征，被称为外化或内化，在调节对这些疾病的易感性方面发挥着重要作用。为了模拟这些遗传倾向，我们选择性地在新环境中饲养大鼠进行高和低探索[饲养高反应者（bHR）与低反应者（bLR）]。为了确定选择反应的基因，我们对538只来自bHR和bLR杂交F2的大鼠进行了表型和基因型分析。一些行为性状表现出高遗传力，包括选择性状：探索运动（EL）在一个新的环境。有显着的表型和遗传之间的相关性测试，捕捉方面的EL和焦虑。尽管巴甫洛夫条件接近（PavCA）行为的遗传力较低，但也存在相关性。10个显着的和条件独立的基因座的6个行为性状。六个特征中的五个反映了EL的不同方面，这些方面被三个行为测试所捕获。从旷场和高架十字迷宫图到不同位点的行进距离测量，因此可以代表新奇诱导的运动活动的不同方面。第六个行为特征，粪便的数量，是唯一的焦虑相关的性状映射到染色体18上的一个显着的位点，其中Pik3c3基因位于。PavCA无显著位点。我们确定了染色体1：95 Mb QTL上Plekhf1基因的一个错义变体，Fancf和Gas2可能是驱动EL性状染色体1：107 Mb QTL的潜在候选基因。在7号染色体上发现了一个与运动活动相关的QTL，包括Pkhd1l1和Trhr基因，这与我们之前发现的这些基因在bHR与bLR大鼠海马中差异表达的结果一致。强遗传性加上与探索性运动和情绪相关的几个位点的鉴定，为这种选择性繁殖的大鼠模型提供了令人信服的支持，发现了与精神病和物质使用障碍固有的内化和外化行为元素相关的相对较大的影响因果变异。
Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment [bred High Responders (bHR) vs. Low Responders (bLR)]. To identify genes underlying the response to selection, we phenotyped and genotyped 538 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.
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