title: The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Mariya
authors.initials: M
authors.lastname: Gonik
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Frank
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Keßler
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Mirjam
authors.initials: M
authors.lastname: Bunck
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Yen
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
authors.forename: Ludwig
authors.initials: L
authors.lastname: Czibere
mesh_terms: D000311:Adrenal Glands / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000503:physiopathology*; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004703:Endocrine System / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D007031:Hypothalamus / Q000503:physiopathology; D008297:Male; D051379:Mice; D010641:Phenotype; D010902:Pituitary Gland / Q000503:physiopathology; D040641:Quantitative Trait Loci / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D005819:Genetic Markers