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

Weber, Heike ; Richter, Jan ; Straube, Benjamin ; Lueken, Ulrike ; Domschke, Katharina ; Schartner, Christoph ; Klauke, Benedikt ; Baumann, Christian ; Pané-Farré, Christiane A. ; Jacob, Christian P. ; Scholz, Claus-Jürgen ; Zwanzger, Peter ; Lang, Thomas ; Fehm, Lydia ; Jansen, Andreas ; Konrad, Carsten ; Fydrich, Thomas ; Wittmann, André ; Pfleiderer, Bettina ; Ströhle, Andreas ; Gerlach, Alexander L. ; Alpers, Georg W. ; Arolt, Volker ; Pauli, Paul ; Wittchen, Hans-Ulrich ; Kent, Lindsey ; Hamm, Alfons O. ; Kircher, Tilo ; Deckert, Jürgen ; Reif, Andreas

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URN: urn:nbn:de:bsz:180-madoc-431600
Document Type: Article
Year of publication: 2016
The title of a journal, publication series: Molecular Psychiatry
Volume: 21
Issue number: 6
Page range: 813-822
Place of publication: New York, NY ; London
Publishing house: Nature Publishing Group ; Macmillan
ISSN: 1359-4184 , 1476-5578
Related URLs:
Publication language: English
Institution: School of Social Sciences > Klinische u. Biologische Psychologie u. Psychotherapie (Alpers 2010-)
Subject: 150 Psychology
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.

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