The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety.
The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety.
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DOI：
10.1186/1471-2164-13-579
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发表时间：
2012-10-31
期刊：
影响因子：
4.4
通讯作者：
Czibere L
中科院分区：
文献类型：
--
作者：
Gonik M;Frank E;Keßler MS;Czamara D;Bunck M;Yen YC;Pütz B;Holsboer F;Bettecken T;Landgraf R;Müller-Myhsok B;Touma C;Czibere L
下丘脑-垂体-肾上腺（HPA）轴在哺乳动物生理应激反应中起重要作用。它的功能障碍与几种精神障碍有关，包括焦虑和抑郁。本研究的目的是确定潜在的HPA轴的内分泌调节的遗传位点。高（HAB）和低（LAB）的焦虑相关行为的小鼠建立了选择性近亲繁殖的CD-1小鼠模型的极端特质焦虑。此外，HAB小鼠与LAB小鼠表现出共病特征，包括应激暴露后皮质酮反应的差异。我们将HAB和LAB品系杂交以产生F1和F2后代。为了确定内分泌表型对总表型方差的贡献，我们通过主成分分析在F2小鼠中检查了多种行为范例以及基于皮质酮分泌的表型。此外，为了确定HPA轴应激反应数量性状的基因组位点，我们在三代家系中进行了基于贝叶斯马尔可夫链蒙特卡罗方法的全基因组多点寡基因连锁分析以及参数连锁分析，然后使用267个单核苷酸多态性（SNP）对自由分离的F2小鼠进行了二维上位性扫描和关联分析，其被鉴定为在HAB和LAB小鼠之间始终不同的遗传标记。HPA轴反应性测量和行为表型由独立的主成分表示，并证明没有相关性。基于这一发现，我们在3号染色体上鉴定了一个单一的数量性状基因座（QTL），该基因座显示出与神经内分泌应激反应连锁（2ln（L-score）> 10，LOD > 23）和显著关联（最低Bonferroni校正p < 10-28）的非常强的证据。连锁峰的位置估计为42.3 cM（95%置信区间：41.3 - 43.3 cM），并显示为上位性（p-调整< 0.004），该基因座位于同一染色体上的35.3 cM。QTL含有参与类固醇合成和心血管效应的基因。3号染色体上的基因组位点对应激诱导的皮质酮分泌的非常显著的影响及其在上位性中的参与突出了该特定位点在HPA轴调节中的关键作用。
The hypothalamic-pituitary-adrenal (HPA) axis is essential to control physiological stress responses in mammals. Its dysfunction is related to several mental disorders, including anxiety and depression. The aim of this study was to identify genetic loci underlying the endocrine regulation of the HPA axis. High (HAB) and low (LAB) anxiety-related behaviour mice were established by selective inbreeding of outbred CD-1 mice to model extremes in trait anxiety. Additionally, HAB vs. LAB mice exhibit comorbid characteristics including a differential corticosterone response upon stress exposure. We crossbred HAB and LAB lines to create F1 and F2 offspring. To identify the contribution of the endocrine phenotypes to the total phenotypic variance, we examined multiple behavioural paradigms together with corticosterone secretion-based phenotypes in F2 mice by principal component analysis. Further, to pinpoint the genomic loci of the quantitative trait of the HPA axis stress response, we conducted genome-wide multipoint oligogenic linkage analyses based on Bayesian Markov chain Monte Carlo approach as well as parametric linkage in three-generation pedigrees, followed by a two-dimensional scan for epistasis and association analysis in freely segregating F2 mice using 267 single-nucleotide polymorphisms (SNPs), which were identified to consistently differ between HAB and LAB mice as genetic markers. HPA axis reactivity measurements and behavioural phenotypes were represented by independent principal components and demonstrated no correlation. Based on this finding, we identified one single quantitative trait locus (QTL) on chromosome 3 showing a very strong evidence for linkage (2ln (L-score) > 10, LOD > 23) and significant association (lowest Bonferroni adjusted p < 10-28) to the neuroendocrine stress response. The location of the linkage peak was estimated at 42.3 cM (95% confidence interval: 41.3 - 43.3 cM) and was shown to be in epistasis (p-adjusted < 0.004) with the locus at 35.3 cM on the same chromosome. The QTL harbours genes involved in steroid synthesis and cardiovascular effects. The very prominent effect on stress-induced corticosterone secretion of the genomic locus on chromosome 3 and its involvement in epistasis highlights the critical role of this specific locus in the regulation of the HPA axis.
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DOI：
10.1111/j.1530-0277.2008.00866.x
发表时间：
2009-03-01
影响因子：
3.2
作者：
Bice, Paula;Valdar, William;Foroud, Tatiana
通讯作者：
Foroud, Tatiana
DOI：
10.1152/ajpregu.00345.2005
发表时间：
2006-04-01
影响因子：
2.8
作者：
Bechtold, AG;Scheuer, DA
通讯作者：
Scheuer, DA
影响因子：
3.7
作者：
Bunck, Mirjam;Czibere, Ludwig;Landgraf, Rainer
通讯作者：
Landgraf, Rainer
影响因子：
3.1
作者：
Belzung, Catherine;Philippot, Pierre
通讯作者：
Philippot, Pierre
影响因子：
29.3
作者：
Cramer, Angelique O. J.;Waldorp, Lourens J.;Borsboom, Denny
通讯作者：
Borsboom, Denny