Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder

Abstract

Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

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

“…rs7209436, which tags rs110402 and rs242924, represents the frequently investigated TAT-haplotype known to predispose to depression 15,16,22,23 , but displayed only suggestive association signals with female PD patients. In line with this, rs7209436 was not associated with PD in two further independent studies 28,29 . Although smaller sample size and mixed-sex analysis may explain this, a comparably small sample revealed a strong association with depression 15 .…”

“…Thus, rs12936181 and/or polymorphisms in high LD may predispose to stress-related disorders in general. For those SNPs that revealed the strongest associations with PD in our current study -rs17689918 and rs17689966 -there is already indirect evidence for effects in anxiety disorders: On the one hand, rs17689918 is in LD with two nominally associated SNPs (rs1396862 and rs1876831) as well as rs878886, the top finding of the Keck study on PD 29 . On the other hand, rs17689966 predisposes to PTSD 14 .…”

“…Most noteworthy, there is consistent evidence that genetic variation interacts with early adverse life events to increase risk for depression [15][16][17][22][23][24][25] . In the context of PD, linkage and case/control studies as well as dimensional association studies provided a heterogeneous picture [26][27][28][29] regarding an involvement of CRHR1. Notably, the initial association of this gene with PD 29 was followed up recently, providing evidence that the CRHR1 minor rs878886 allele leads to fearacquisition deficits using a fear condition protocol in healthy volunteers 30 .…”

“…In the context of PD, linkage and case/control studies as well as dimensional association studies provided a heterogeneous picture [26][27][28][29] regarding an involvement of CRHR1. Notably, the initial association of this gene with PD 29 was followed up recently, providing evidence that the CRHR1 minor rs878886 allele leads to fearacquisition deficits using a fear condition protocol in healthy volunteers 30 . Furthermore, a neuroimaging study revealed that the processing of emotional stimuli crucially depends on CRHR1 genotype 31 .…”

Family-Based Study of AVPR1B Association and Interaction with Stressful Life Events on Depression and Anxiety in Suicide Attempts

“…Single nucleotide polymorphisms (SNPs) and haplotypes in AVPR1B were previously observed to associate with stressrelated mood and anxiety disorders (van West et al, 2004;Dempster et al, 2007;Keck et al, 2008;van West et al, 2009;Leszczynska-Rodziewicz et al, 2012). AVPR1B knockout in animal models suggest that the gene is involved in response to multiple stressors, in addition to chronic stressors (Roper et al, 2011).…”