title: CRHR1 promoter hypomethylation: An epigenetic readout of panic disorder?
abstract: The corticotropin releasing hormone receptor 1 (CRHR1) is crucially involved in the hypothalamic-pituitary-adrenal axis and thus a major regulator of the stress response. CRHR1 gene variation is associated with several mental disorders including anxiety disorders. Studies in rodents have demonstrated epigenetic regulation of CRHR1 gene expression to moderate response to stressful environment. In the present study, we investigated CRHR1 promoter methylation for the first time regarding its role in panic disorder applying a case-control approach (N=131 patients, N=131 controls). In an independent sample of healthy volunteers (N=255), CRHR1 methylation was additionally analyzed for association with the Beck Anxiety Inventory (BAI) score as a dimensional panic-related intermediate phenotype. The functional relevance of altered CRHR1 promoter methylation was investigated by means of luciferase-based reporter gene assays. In panic disorder patients, a significantly decreased CRHR1 methylation was discerned (p<0.001). Accordingly, healthy controls with high BAI scores showed significantly decreased CRHR1 methylation. Functional analyses revealed an increased gene expression in presence of unmethylated as compared to methylated pCpGl_CRHR1 reporter gene vectors. The present study identified a potential role of CRHR1 hypomethylation - conferring increased CRHR1 expression - in panic disorder and a related dimensional intermediate phenotype. This up-regulation of CRHR1 gene expression driven by de-methylation might constitute a link between the stress response and panic disorder risk.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schartner
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Ziegler
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Schiele
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Kollert
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zwanzger
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Psychology (Biological Psychology, Clinical Psychology and Psychotherapy), University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Pauli
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany; Department of Psychiatry, University of Freiburg, Freiburg, Germany. Electronic address: katharina.domschke@uniklinik-freiburg.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
mesh_terms: D000328:Adult; D016009:Chi-Square Distribution; D003198:Computer Simulation; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: Beck Anxiety Inventory; Corticotropin releasing hormone receptor 1; Epigenetics; HPA axis; Methylation; Panic disorder