Childhood maltreatment, the corticotropin‐releasing hormone receptor gene and adult depression in the general population

Grabe, Hans J.; Schwahn, Christian; Appel, Katja; Mahler, Jessie; Schulz, Andrea; Spitzer, Carsten; Fenske, Kristin; Barnow, Sven; Lucht, Michael; Freyberger, Harald J.; John, Ulrich; Teumer, Alexander; Wallaschofski, Henri; Nauck, Matthias; Völzke, Henry

doi:10.1002/ajmg.b.31131

Cited by 102 publications

(73 citation statements)

References 45 publications

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“…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 .…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…For example, children who were highly reactive to acute stress were healthier and had fewer injury incidences than children who showed lowerstress reactivity (Boyce et al, 1995;Boyce, 1996) in moderately stressful settings. It is possible that because these highly reac- Depression; SLE A protective Heim et al, 2009;Polanczyk et al, 2009;Kranzler et al, 2011) Depression, neuroticism; SLE A risk (Grabe et al, 2010;DeYoung et al, 2011;Laucht et al, 2013 tive individuals are more sensitive to the environment, they are more likely to detect stress and develop regulatory functions accordingly, compared with less-sensitive individuals. However, the advantage of stress sensitivity in G homozygotes in developing regulatory functions may not exist in a very lowstress environment, because emotion regulation is not needed.…”

Section: Discussionmentioning

confidence: 99%

Indirect Effect of Corticotropin-Releasing Hormone Receptor 1 Gene Variation on Negative Emotionality and Alcohol Use via Right Ventrolateral Prefrontal Cortex

Glaser¹,

Zubieta

Hsu

et al. 2014

J. Neurosci.

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Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p (FWE corrected) Ͻ 0.01, N ϭ 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p Ͻ 0.05, N ϭ 69) was observed, which was further moderated by childhood stress (p Ͻ 0.05, N ϭ 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p Ͻ 0.05, N ϭ 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.

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“…1). Another group examined SNPs in CRHR1 in a large population sample [Grabe et al, 2010]. They detected a significant moderator effect of the TAT haplotype on the risk of adult depression symptoms.…”

Section: Discussionmentioning

confidence: 99%

Erratum: Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population

Ishitobi¹,

Nakayama²,

Yamaguchi³

et al. 2012

American J of Med Genetics Pt B

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Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic-pituitary-adrenal axis, including the corticotrophin-releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) (rs4076452, rs7209436, rs110402, rs242924, rs242940, and rs173365 for CRHR1 and rs4722999, rs3779250, rs2267710, rs1076292, rs2284217, and rs226771 for CRHR2) in MDD patients (n ¼ 173), PD patients (n ¼ 180), and healthy controls (n ¼ 285). The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T-A-T-G-G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T-A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C-C haplotype consisting of rs4722999 and rs3779250 in CRHR2 was associated with PD. These results provide support for an association of CRHR1 and CRHR2 with MDD and PD.

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Childhood maltreatment, the corticotropin‐releasing hormone receptor gene and adult depression in the general population

Cited by 102 publications

References 45 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

Indirect Effect of Corticotropin-Releasing Hormone Receptor 1 Gene Variation on Negative Emotionality and Alcohol Use via Right Ventrolateral Prefrontal Cortex

Erratum: Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population

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