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

Article metrics

Abstract

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic–pituitary–adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. 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 risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk 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 gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. 1

    Holsboer F, Ising M . Central CRH system in depression and anxiety—evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol 2008; 583: 350–357.

  2. 2

    Refojo D, Holsboer F . CRH signaling. Molecular specificity for drug targeting in the CNS. Ann NY Acad Sci 2009; 1179: 106–119.

  3. 3

    Aguilera G, Nikodemova M, Wynn PC, Catt KJ . Corticotropin releasing hormone receptors: two decades later. Peptides 2004; 25: 319–329.

  4. 4

    Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 1998; 19: 162–166.

  5. 5

    Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 2003; 6: 1100–1107.

  6. 6

    Wang XD, Chen Y, Wolf M, Wagner KV, Liebl C, Scharf SH et al. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol Dis 2011; 42: 300–310.

  7. 7

    Wang XD, Labermaier C, Holsboer F, Wurst W, Deussing JM, Muller MB et al. Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur J Neurosci 2012; 36: 2360–2367.

  8. 8

    Thoeringer CK, Henes K, Eder M, Dahlhoff M, Wurst W, Holsboer F et al. Consolidation of remote fear memories involves Corticotropin-Releasing Hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus. Neuropsychopharmacology 2012; 37: 787–796.

  9. 9

    Bao AM, Swaab DF . Corticotropin-releasing hormone and arginine vasopressin in depression focus on the human postmortem hypothalamus. Vitam Horm 2010; 82: 339–365.

  10. 10

    Holsboer F, Ising M . Stress hormone regulation: biological role and translation into therapy. Annu Rev Psychol 2010; 61: 81–109, C101-C111.

  11. 11

    Spijker AT, van Rossum EF . Glucocorticoid sensitivity in mood disorders. Neuroendocrinology 2012; 95: 179–186.

  12. 12

    Thorsell A . Brain neuropeptide Y and corticotropin-releasing hormone in mediating stress and anxiety. Exp Biol Med (Maywood) 2010; 235: 1163–1167.

  13. 13

    Amstadter AB, Nugent NR, Yang BZ, Miller A, Siburian R, Moorjani P et al. Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients. Dis Markers 2011; 30: 89–99.

  14. 14

    White S, Acierno R, Ruggiero KJ, Koenen KC, Kilpatrick DG, Galea S et al. Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults. J Anxiety Disord 2013; 27: 678–683.

  15. 15

    Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 2008; 65: 190–200.

  16. 16

    Grabe HJ, Schwahn C, Appel K, Mahler J, Schulz A, Spitzer C et al. Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1483–1493.

  17. 17

    Heim C, Bradley B, Mletzko TC, Deveau TC, Musselman DL, Nemeroff CB et al. Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front Behav Neurosci 2009; 3: 41.

  18. 18

    Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci Lett 2006; 404: 358–362.

  19. 19

    Ressler KJ, Bradley B, Mercer KB, Deveau TC, Smith AK, Gillespie CF et al. Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 812–824.

  20. 20

    Wasserman D, Wasserman J, Rozanov V, Sokolowski M . Depression in suicidal males: genetic risk variants in the CRHR1 gene. Genes Brain Behav 2009; 8: 72–79.

  21. 21

    DeYoung CG, Cicchetti D, Rogosch FA . Moderation of the association between childhood maltreatment and neuroticism by the corticotropin-releasing hormone receptor 1 gene. J Child Psychol Psychiatry 2011; 52: 898–906.

  22. 22

    Laucht M, Treutlein J, Blomeyer D, Buchmann AF, Schmidt MH, Esser G et al. Interactive effects of corticotropin-releasing hormone receptor 1 gene and childhood adversity on depressive symptoms in young adults: findings from a longitudinal study. Eur Neuropsychopharmacol 2013; 23: 358–367.

  23. 23

    Kranzler HR, Feinn R, Nelson EC, Covault J, Anton RF, Farrer L et al. A CRHR1 haplotype moderates the effect of adverse childhood experiences on lifetime risk of major depressive episode in African-American women. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 960–968.

  24. 24

    Liu Z, Liu W, Yao L, Yang C, Xiao L, Wan Q et al. Negative life events and corticotropin-releasing-hormone receptor1 gene in recurrent major depressive disorder. Sci Rep 2013; 3: 1548.

  25. 25

    Polanczyk G, Caspi A, Williams B, Price TS, Danese A, Sugden K et al. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch Gen Psychiatry 2009; 66: 978–985.

  26. 26

    Hodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O et al. Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 65–73.

  27. 27

    Ishitobi Y, Nakayama S, Kanehisa M, Higuma H, Maruyama Y, Okamoto S et al. Association between corticotropin-releasing hormone receptor 1 and 2 (CRHR1 and CRHR2) gene polymorphisms and personality traits. Psychiatr Genet 2013; 23: 255–257.

  28. 28

    Ishitobi Y, Nakayama S, Yamaguchi K, Kanehisa M, Higuma H, Maruyama Y et al. Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 429–436.

  29. 29

    Keck ME, Kern N, Erhardt A, Unschuld PG, Ising M, Salyakina D et al. Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1196–1204.

  30. 30

    Heitland I, Groenink L, Bijlsma EY, Oosting RS, Baas JM . Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter. PLoS One 2013; 8: e63772.

  31. 31

    Hsu DT, Mickey BJ, Langenecker SA, Heitzeg MM, Love TM, Wang H et al. Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing. J Neurosci 2012; 32: 3253–3260.

  32. 32

    Reif A, Weber H, Domschke K, Klauke B, Baumann C, Jacob CP et al. Meta-analysis argues for a female-specific role of MAOA-uVNTR in panic disorder in four European populations. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 786–793.

  33. 33

    Mannuzza S, Fyer AJ, Klein DF, Endicott J . Schedule for Affective Disorders and Schizophrenia—Lifetime Version modified for the study of anxiety disorders (SADS-LA): rationale and conceptual development. J Psychiatr Res 1986; 20: 317–325.

  34. 34

    Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J et al. The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 1988; 45: 1069–1077.

  35. 35

    Wittchen HU, Garczynski E, Pfister H . Composite International Diagnostic Interview According to ICD-10 and DSM-IV. Hogrefe: : Göttingen, Germany, 1997.

  36. 36

    Gloster AT, Wittchen HU, Einsle F, Hofler M, Lang T, Helbig-Lang S et al. Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia. Eur Arch Psychiatry Clin Neurosci 2009; 259 (Suppl 2): S155–S166.

  37. 37

    Domschke K, Reif A, Weber H, Richter J, Hohoff C, Ohrmann P et al. Neuropeptide S receptor gene — converging evidence for a role in panic disorder. Mol Psychiatry 2010; 16: 938–948.

  38. 38

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 (Suppl 20): 22–33.

  39. 39

    Chambless DL, Caputo GC, Bright P, Gallagher R . Assessment of fear of fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions questionnaire. J Consult Clin Psychol 1984; 52: 1090–1097.

  40. 40

    Reiss S, Peterson RA, Gursky DM, McNally RJ . Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther 1986; 24: 1–8.

  41. 41

    Taylor S, Zvolensky MJ, Cox BJ, Deacon B, Heimberg RG, Ledley DR et al. Robust dimensions of anxiety sensitivity: development and initial validation of the Anxiety Sensitivity Index-3. Psychol Assess 2007; 19: 176–188.

  42. 42

    Weber H, Klamer D, Freudenberg F, Kittel-Schneider S, Rivero O, Scholz CJ et al. The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis. Eur Neuropsychopharmacol 2013; 24: 65–85.

  43. 43

    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.

  44. 44

    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

  45. 45

    Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

  46. 46

    Menashe I, Rosenberg PS, Chen BE . PGA: power calculator for case-control genetic association analyses. BMC Genet 2008; 9: 36.

  47. 47

    Ramakers C, Ruijter JM, Deprez RH, Moorman AF . Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 2003; 339: 62–66.

  48. 48

    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3: RESEARCH0034.

  49. 49

    Kircher T, Arolt V, Jansen A, Pyka M, Reinhardt I, Kellermann T et al. Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder. Biol Psychiatry 2013; 73: 93–101.

  50. 50

    Reinhardt I, Jansen A, Kellermann T, Schuppen A, Kohn N, Gerlach AL . Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. Eur Arch Psychiatry Clin Neurosci 2010; 260: 443–453.

  51. 51

    Lueken U, Straube B, Konrad C, Wittchen HU, Strohle A, Wittmann A et al. Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia. Am J Psychiatry 2013; 170: 1345–1355.

  52. 52

    Lueken U, Straube B, Reinhardt I, Maslowski NI, Wittchen HU, Strohle A et al. Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia. Psychol Med 2013; 44: 381–394.

  53. 53

    Straube B, Reif A, Richter J, Lueken U, Weber H, Arolt V et al. The functional -1019C/G HTR1A polymorphism and mechanisms of fear. Transl Psychiatry 2014; 4: e490.

  54. 54

    Richter J, Hamm AO, Pane-Farre CA, Gerlach AL, Gloster AT, Wittchen HU et al. Dynamics of defensive reactivity in patients with panic disorder and agoraphobia: implications for the etiology of panic disorder. Biol Psychiatry 2012; 72: 512–520.

  55. 55

    Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C . Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67.

  56. 56

    Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 2005; 21: 2933–2942.

  57. 57

    Hiard S, Charlier C, Coppieters W, Georges M, Baurain D . Patrocles: a database of polymorphic miRNA-mediated gene regulation in vertebrates. Nucleic Acids Res 2010; 38 (Database issue): D640–D651.

  58. 58

    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE . Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593–602.

  59. 59

    Lappalainen T, Sammeth M, Friedlander MR, 't Hoen PA, Monlong J, Rivas MA et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 2013; 501: 506–511.

  60. 60

    Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 2010; 6: e1000952.

  61. 61

    Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L et al. A survey of genetic human cortical gene expression. Nat Genet 2007; 39: 1494–1499.

  62. 62

    Hamm AO, Richter J, Pané-Farré CA . When the threat comes from inside the body. A neuroscience based learning perspective of the etiology of panic disorder. Restor Neurol Neurosci 2013; 32: 79–93.

  63. 63

    Davis M, Walker DL, Miles L, Grillon C . Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 2010; 35: 105–135.

  64. 64

    Schulkin J, Morgan MA, Rosen JB . A neuroendocrine mechanism for sustaining fear. Trends Neurosci 2005; 28: 629–635.

  65. 65

    Walker DL, Miles LA, Davis M . Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 1291–1308.

  66. 66

    Sink KS, Walker DL, Freeman SM, Flandreau EI, Ressler KJ, Davis M . Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry 2013; 18: 308–319.

  67. 67

    Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry 2010; 167: 47–55.

  68. 68

    McTeague LM, Lang PJ, Laplante MC, Bradley MM . Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology. Biol Psychiatry 2011; 70: 415–424.

Download references

Acknowledgements

We thank all individuals who participated in this study. We credit the MRC Sudden Death Brain and Tissue Bank, Edinburgh, Scotland for providing brain tissue samples examined in this study. This work is part of the German multicenter trial ‘Mechanisms of Action in CBT (MAC)’. The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The principal investigators (PIs) of the centers with respective areas of responsibility in the MAC study are: V Arolt (Münster: Overall MAC Program Coordination), H-U Wittchen (Dresden: PI for the Randomized Clinical Trial and Manual Development), A Hamm (Greifswald: PI for Psychophysiology), AL Gerlach (Münster: PI for Psychophysiology and Panic subtypes), A Ströhle (Berlin: PI for Experimental Pharmacology), T Kircher (Marburg: PI for functional neuroimaging), and J Deckert (Würzburg: PI for Genetics). Additional site directors in the randomized controlled trial component of the program are as follows: GW Alpers (Würzburg), T Fydrich and L Fehm (Berlin-Adlershof), and T Lang (Bremen). The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW and C-JS; HA1593/15-1 to AH and CP-F). T Töpner, N Steigerwald, C Gagel and J Auer are credited for excellent technical assistance.

Author information

Correspondence to H Weber.

Ethics declarations

Competing interests

V Arolt is a member of the advisory boards and/or gave presentations for the following companies: Astra-Zeneca, Eli Lilly, Janssen-Organon, Lundbeck, Otsuka, Servier, and Trommsdorff. He also received research grants from Astra-Zeneca, Lundbeck and Servier. He chaired the committee for the ‘Wyeth Research Award Depression and Anxiety’. J Deckert received in the past 3 years honoraria by Janssen, Bristol Myers-Squibb, Wyeth, Lundbeck, Astra-Zeneca and Pfizer and Grant Support by Medice, Lundbeck and Astra-Zeneca. T Kircher received fees for educational programs from Janssen, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb, Pfitzer and Astra-Zeneca; travel support/sponsorship for congresses from Servier; speaker's honoraria from Janssen; and research grants from Pfizer and Lundbeck. C Konrad received fees for educational programs from Esparma/Aristo Pharma GmbH, Eli Lilly, Servier and MagVenture. A Reif has received research support from PsyNova, and A Reif and K Domschke have received research grants from Astra Zeneca. K Domschke has received honoraria for scientific talks from Pfizer, Lilly and Bristol-Myers Squibb and has been a consultant for Johnson&Johnson. A Ströhle received research funding from the German Federal Ministry of Education and Research, the European Commission (FP6) and Lundbeck and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth and UCB. He was a consultant for Actelion. Educational grants were given by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds, the Eli Lilly International Foundation, Janssen-Cilag, Pfizer and Eli Lilly. H-U Wittchen has served as a general consultant (non-product related) for Pfizer, Organon, Servier and EssexPharma and has received grant funding for his institution from Sanofi Aventis, Pfizer, Lundbeck, Novatis, Essex Pharma, Servier and Wyeth. These cooperations have no relevance to the work that is covered in the manuscript. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Supplementary Information (DOCX 129 kb)

PowerPoint slides

PowerPoint slide for Fig. 1

PowerPoint slide for Fig. 2

PowerPoint slide for Fig. 3

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading