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Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
- Source :
- Translational Psychiatry, Vol 9, Iss 1, Pp 1-13 (2019), Translational Psychiatry, Translational Psychiatry, 1(9):75
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
- Subjects :
- Adult
Male
0301 basic medicine
Oncology
medicine.medical_specialty
Hamilton Anxiety Rating Scale
medicine.medical_treatment
behavioral disciplines and activities
Article
Arousal
lcsh:RC321-571
Young Adult
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Orexin Receptors
Internal medicine
Outcome Assessment, Health Care
Avoidance Learning
medicine
Humans
ddc:610
Allele
Agoraphobia
Cerebrum
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Biological Psychiatry
Cognitive Behavioral Therapy
business.industry
Panic disorder
Case-control study
Fear
Middle Aged
medicine.disease
Magnetic Resonance Imaging
Cognitive behavioral therapy
Psychiatry and Mental health
Phenotype
030104 developmental biology
Case-Control Studies
Panic Disorder
Anxiety
Female
medicine.symptom
business
Personalized medicine
Human behaviour
Predictive markers
Molecular neuroscience
Psychiatric disorders
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 21583188
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Translational Psychiatry
- Accession number :
- edsair.doi.dedup.....8b1f2e530dc1f3624d69f62a698374b0