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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- 作者：Mariya Gonik (1) (2)
Elisabeth Frank (1)
Melanie S Ke?ler (1)
Darina Czamara (1)
Mirjam Bunck (1)
Yi-Chun Yen (1)
Benno Pütz (1)
Florian Holsboer (1)
Thomas Bettecken (1)
Rainer Landgraf (1)
Bertram Müller-Myhsok (1)
Chadi Touma (1)
Ludwig Czibere (1) - 关键词：F2 ; Corticosterone ; Stress response ; HPA axis ; QTL
- 刊名：BMC Genomics
- 出版年：2012
- 出版时间：December 2012
- 年：2012
- 卷：13
- 期：1
- 全文大小：559KB
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Elisabeth Frank (1)
Melanie S Ke?ler (1)
Darina Czamara (1)
Mirjam Bunck (1)
Yi-Chun Yen (1)
Benno Pütz (1)
Florian Holsboer (1)
Thomas Bettecken (1)
Rainer Landgraf (1)
Bertram Müller-Myhsok (1)
Chadi Touma (1)
Ludwig Czibere (1)
1. Max Planck Institute of Psychiatry, Munich, Germany
2. Institute for Stroke and Dementia Research, Ludwig Maximilian University, Munich, Germany
文摘
Background 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. Method 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. Results 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. Conclusion 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.