Our paper entitled “A polymorphism in the crhr1 gene determines stress vulnerability in male mice” has been accepted by Endocrinology!
Abstract:
Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform longterm effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse corticotropin releasing hormone receptor 1 (crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows us a better understanding of the currently reported GxE interactions of early trauma and crhr1 in humans. We identified an intronic genetic variant in the mouse crhr1 locus, rs27040842, that modulates the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, as crhr1 mRNA expression and CRHR1 receptor binding was enhanced in these animals. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep-sequencing of the crhr1 locus in CD1 mice revealed a large number of linked variants with some located in important regulatory regions, similar to the location of human crhr1 variants implicated in modulating GxE interactions. Our data support that the described gene x stress exposure interaction in this animal model is based on naturally occurring genetic variations in the crhr1 gene associated with enhanced CRHR1 mediated signaling. Our results suggest that patients with a specific genetic predisposition in the crhr1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.