Weber, H., Richter, J., Straube, B., Lueken, U., Domschke, K., Schartner, C., Klauke, B., Baumann, C., Pane-Farre, C., Jacob, C. P., Scholz, C-J, Zwanzger, P., Lang, T., Fehm, L., Jansen, A., Konrad, C., Fydrich, T., Wittmann, A., Pfleiderer, B., Stroehle, A., Gerlach, A. L., Alpers, G. W., Arolt, V., Pauli, P., Wittchen, H-U, Kent, L., Hamm, A., Kircher, T., Deckert, J. and Reif, A. (2016). Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Mol. Psychiatr., 21 (6). S. 813 - 823. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5578

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Weber, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straube, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lueken, U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domschke, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schartner, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klauke, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pane-Farre, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jacob, C. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholz, C-JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwanzger, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fehm, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konrad, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fydrich, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittmann, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfleiderer, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroehle, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerlach, A. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alpers, G. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arolt, V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauli, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittchen, H-UUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kent, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamm, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kircher, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-274714
DOI: 10.1038/mp.2015.125
Journal or Publication Title: Mol. Psychiatr.
Volume: 21
Number: 6
Page Range: S. 813 - 823
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5578
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CORTICOTROPIN-RELEASING-HORMONE; RECEPTOR 1 GENE; COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSIVE DISORDER; ANXIETY-RELATED BEHAVIOR; ADULT DEPRESSION; CHILDHOOD MALTREATMENT; DSM-IV; ASSOCIATION; STRESSMultiple languages
Biochemistry & Molecular Biology; Neurosciences; PsychiatryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27471

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