title: Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter--revisited.
abstract: We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears.
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht, The Netherlands.|Helmholtz Research Institute, Utrecht, The Netherlands.
authors.forename: I
authors.identifier: http://orcid.org/0000-0002-6672-7857
authors.initials: I
authors.lastname: Heitland
authors.affiliation: Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Groenink
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: van Gool
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-0992-634X
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Experimental Psychology, Utrecht University, Utrecht, The Netherlands.|Helmholtz Research Institute, Utrecht, The Netherlands.
authors.forename: J M P
authors.initials: JM
authors.lastname: Baas
mesh_terms: D000328:Adult; D001007:Anxiety / Q000235:genetics; D001008:Anxiety Disorders / Q000235:genetics*; D003214:Conditioning, Classical; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D005239:Fear / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D050486:Serotonin Plasma Membrane Transport Proteins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: CRHR1; Corticotropin-releasing factor; corticotropin-releasing hormone; fear conditioning; fear-potentiated startle; replication study; rs878886