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Mol Psychiatry. 2017 Oct;22(10):1431-1439. doi: 10.1038/mp.2017.2. Epub 2017 Feb 7.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

Author information

1
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
2
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
3
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
4
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Department of Psychology, University of Greifswald, Greifswald, Germany.
6
Department of Psychology, and Center of Mental Health, University of Würzburg, Würzburg, Germany.
7
Donders Institute for Brain Cognition and Behavior, Departments of Psychiatry, Human Genetics and Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Interdisciplinary Center for Clinical Research, Department of Clinical and Molecular Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
9
School of Medicine, University of St Andrews, St Andrews, UK.
10
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
11
Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
12
Division of Medical Genetics, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.
13
Department of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
14
Department of Psychiatry and Psychotherapy, University Hospital of Münster, Münster, Germany.
15
Department of Psychiatry and Psychotherapy, District Hospital Gabersee, Wasserburg, Germany.
16
Department of Psychiatry Radboud University Medical Center, Nijmegen, The Netherlands.
17
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmwegen, The Netherlands.
18
Department of Psychology, University of Regensburg, Regensburg, Germany.
19
Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
20
Department of Psychology, Humboldt University, Berlin, Germany.
21
Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
22
Department of Psychiatry and Psychotherapy, University Hospital of Marburg, Marburg, Germany.
23
Department of Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany.
24
Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany.
25
Department of Psychology, University of Hamburg, Hamburg, Germany.
26
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
27
Neuroimaging Center (NIC) und Deutsches Resilienz-Zentrum (DRZ), Johannes Gutenberg University Medical Center, Mainz, Germany.
28
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Abstract

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

PMID:
28167838
DOI:
10.1038/mp.2017.2
[Indexed for MEDLINE]

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