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

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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.

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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.

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Correspondence to H Weber.

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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.

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