Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression

Liu, Zhongchun; Zhu, Fan; Wang, Gaohua; Xiao, Zheman; Wang, Huiling; Tang, Jihua; Wang, Xiaoping; Qiu, De-sheng; Liu, Wanhong; Cao, Zhijian; Li, Wenxin

doi:10.1016/j.neulet.2006.06.016

Cited by 130 publications

(83 citation statements)

References 32 publications

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“…Accordingly, targeted association studies were conducted to test whether CRHR1 polymorphisms -mainly rs7209436, rs110402, and rs242924, forming a haplotype where the TAT combination conveys disease -influence the risk for stress-related disorders like post-traumatic-stress disorder (PTSD; 13,14 ) and depression [15][16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…6 An additional argument for the direct involvement of CRF in the symptomatology of depression is the recently found increased susceptibility to MD in case of a single-nucleotide polymorphisms in the CRF receptor 1 (CRFR1) gene. 7,8 Antidepressants attenuate the synthesis of CRF by upregulation of corticosteroid receptor expression 1 that causes a decrease of the cerebrospinal fluid (CSF) levels of CRF. 9 A transgenic mouse model with an overproduction of CRF showed increased anxiogenic behavior, a symptom that is usually related with MD, and that could be counteracted by injection of a CRF antagonist.…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

et al. 2008

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Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-b and tumor necrosis factor-a, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-a, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.

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“…Patients with depression exhibit elevated CRH mRNA and peptide levels [3,4] , suggesting that the hyperactivity of CRH-containing neurons is associated with, or contributes to the pathophysiology of depression. This idea is reinforced by the following observations: (1) CRH level is increased in cerebral spinal fluid of depressed patients [5] ; (2) Antidepressant drugs can decrease HPA-axis activity [6] ; (3) CRH injection into the brain of laboratory animals induces signs and symptoms of major depression, and the same syndromes are observed in transgenic mice in which CRH is over-produced [7] ; (4) The finding that single-nucleotide polymorphisms (SNPs) in CRH receptor1 gene (CRHR1) are associated with increased susceptibility to major depression [8] is an argument for the direct involvement of CRH in the symptomatology of depression. The behavioral response to stress is associated with CRH changes in the central nervous system (CNS) [9] .…”

Section: Introductionmentioning

confidence: 99%

Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress

et al. 2010

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Objective Corticotropin-releasing hormone (CRH) plays an important role in neuroendocrine, autonomic and behavioral responses to stressors. In the present study, the effect of chronic unpredictable mild stress (CUMS) on CRH neurons was investigated in rat brain. Methods The rats were exposed to one of the stressors each day for 21 d. Immunostaining was performed to detect the CRH-positive neurons in the paraventricular nucleus (PVN) of the hypothalamus and in amygdala.Results After the stress protocol, the animals showed a reduction in body weight gain as well as reduced sucrose preference and locomotor activity. Interestingly, the CRH neurons in both PVN and central nucleus of the amygdala (CeA) were stimulated by CUMS. The densities of CRH-containing neurons in both PVN and CeA were significantly higher than those in control group. Conclusion The CRH systems in PVN and CeA may both contribute to depression-like behaviors during CUMS.

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Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression

Cited by 130 publications

References 32 publications

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

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

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress

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