Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

Abstract

Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD).Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (p rs17689918 =1.3*10 -4 ; p rs17689966 =0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala.Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

“…31 CRHR1 encodes a G protein-coupled receptor for neuropeptides involved in diverse physiological processes including stress and immune responses. 32 Overall, these data strongly suggest that the H1 MAPT -haplotype contributes to increased risk for FTD and PD and its effect is likely mediated by modulating changes in the expression profiles of functionally important cis -genes.…”

A Cortical Circuit for Sexually Dimorphic Oxytocin-Dependent Anxiety Behaviors

“…Genetic studies have established that loss of Crhr1 in glutamatergic cells in the cerebral cortex is anxiolytic (Refojo et al, 2011), and that CRH dysfunction can contribute to human anxiety related disorders (Weber et al, 2015; Smoller, 2016). Although no data suggesting an interaction of the OXT/OXTR and CRH/CRHR1 systems in the cerebral cortex has been reported previously, the specific and high expression of Crhbp in OxtrINs suggested to us that the anxiogenic effects of CRH on layer 2/3 pyramidal cells might be modulated by release of CRHBP from OxtrINs, and that differential sensitivity of this system may account for the male specific anxiolytic effects of OxtrINs activation.…”

Functional neuroanatomy in panic disorder: Status quo of the research

“…Preclinical and clinical studies have indicated that CRHR1 is a possible candidate gene for mood and anxiety disorders[79,125,126]. Weber et al[127] studied different variants located within the CRHR1 gene with regard to possible associations with PD. Genotyping in 531 matched case/control pairs (PD patients and healthy control subjects) revealed 9 single nucleotide polymorphisms (SNPs).…”

“…The risk allele carriers showed aberrant fear conditioning predominantly in the bilateral prefrontal cortex and altered safety signal processing in the amygdala, suggesting existing fear sensitization and sustained fear. Furthermore, in this multilevel study, Weber et al[127] performed an expression analysis of CRHR1 gene. For this purpose, postmortem tissue of 76 deceased individuals obtained from the MRC Sudden Death Brain and Tissue Bank, Edinburgh, United Kingdom, was analyzed.…”

“…Preclinical and clinical studies have indicated that CRHR1 is a possible candidate gene for PD[125,126]. In a multi-level study by Weber et al[127], one allele was found to increase risk for PD in females. Aberrant fear conditioning due to CRHR1 variation was demonstrated in PD as well as in healthy subjects.…”