Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing
| Autor: | Thomas Lang, Alfons O. Hamm, Bettina Pfleiderer, Claus-Jürgen Scholz, Jan Richter, Christiane A. Pané-Farré, Jürgen Deckert, Benjamin Straube, Hans-Ulrich Wittchen, Volker Arolt, Heike Weber, Alexander L. Gerlach, Andreas Ströhle, Paul Pauli, Benedikt Klauke, Christian Jacob, Tilo Kircher, Lydia Fehm, Carsten Konrad, Lindsey Kent, Thomas Fydrich, Andreas Jansen, Peter Zwanzger, Christian Baumann, Ulrike Lueken, André Wittmann, Katharina Domschke, C. Schartner, Andreas Reif, Georg W. Alpers |
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| Přispěvatelé: | University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences |
| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine Avoidance test Candidate gene Hydrocortisone Corticotropin-Releasing Hormone Pituitary-Adrenal System Anxiety 0302 clinical medicine Risk Factors Medicine R2C Panic disorder fMRI ~DC~ Fear Middle Aged Anxiety Disorders Association study Psychiatry and Mental health Phenotype Schizophrenia Panic Disorder Female medicine.symptom BDC RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry Adult Hypothalamo-Hypophyseal System medicine.medical_specialty Genotype NDAS Single-nucleotide polymorphism Polymorphism Single Nucleotide Receptors Corticotropin-Releasing Hormone 03 medical and health sciences Cellular and Molecular Neuroscience Bias Internal medicine Humans Genetic Predisposition to Disease Allele Molecular Biology Alleles business.industry Genetic Variation CRHR1 medicine.disease Minor allele frequency 030104 developmental biology Endocrinology MCP RC0321 Anxiety sensitivity business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Molecular Psychiatry. 21:813-822 |
| ISSN: | 1476-5578 1359-4184 |
| DOI: | 10.1038/mp.2015.125 |
| Popis: | 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 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, JR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW). Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. 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 candidate molecule in panic disorder (PD). Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (prs17689918=1.3*10-4; prs17689966=0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala. Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) 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 CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias 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. Postprint |
| Databáze: | OpenAIRE |
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