Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Weber, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richter, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Straube, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lueken, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Domschke, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schartner, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klauke, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pane-Farre, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacob, C. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scholz, C-J UNSPECIFIED UNSPECIFIED UNSPECIFIED Zwanzger, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lang, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fehm, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jansen, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Konrad, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fydrich, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittmann, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfleiderer, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroehle, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerlach, A. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alpers, G. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arolt, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauli, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittchen, H-U UNSPECIFIED UNSPECIFIED UNSPECIFIED Kent, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamm, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kircher, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reif, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language CORTICOTROPIN-RELEASING-HORMONE; RECEPTOR 1 GENE; COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSIVE DISORDER; ANXIETY-RELATED BEHAVIOR; ADULT DEPRESSION; CHILDHOOD MALTREATMENT; DSM-IV; ASSOCIATION; STRESS Multiple languages Biochemistry & Molecular Biology; Neurosciences; Psychiatry Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27471