GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.
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.
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
J
J
Deckert
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.|Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
H
H
Weber
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
C
C
Villmann
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
T B
TB
Lonsdorf
Department of Psychology, University of Greifswald, Greifswald, Germany.
J
J
Richter
Department of Psychology, and Center of Mental Health, University of Würzburg, Würzburg, Germany.
M
M
Andreatta
Donders Institute for Brain Cognition and Behavior, Departments of Psychiatry, Human Genetics and Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
A
A
Arias-Vasquez
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.|Interdisciplinary Center for Clinical Research, Department of Clinical and Molecular Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
L
L
Hommers
School of Medicine, University of St Andrews, St Andrews, UK.
L
L
Kent
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
C
C
Schartner
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
S
S
Cichon
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
C
C
Wolf
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
N
N
Schaefer
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
C R
CR
von Collenberg
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
B
B
Wachter
Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany.
R
R
Blum
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
D
D
Schümann
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
R
R
Scharfenort
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
J
J
Schumacher
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
A J
AJ
Forstner
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
C
C
Baumann
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
M A
MA
Schiele
Department of Psychiatry and Psychotherapy, University Hospital of Münster, Münster, Germany.
S
S
Notzon
Department of Psychiatry and Psychotherapy, University Hospital of Münster, Münster, Germany.|Department of Psychiatry and Psychotherapy, District Hospital Gabersee, Wasserburg, Germany.
P
P
Zwanzger
Department of Psychiatry Radboud University Medical Center, Nijmegen, The Netherlands.
J G E
JGE
Janzing
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmwegen, The Netherlands.
T
T
Galesloot
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmwegen, The Netherlands.
L A
LA
Kiemeney
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
A
A
Gajewska
Department of Psychology, and Center of Mental Health, University of Würzburg, Würzburg, Germany.
E
E
Glotzbach-Schoon
Department of Psychology, University of Regensburg, Regensburg, Germany.
A
A
Mühlberger
Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
G
G
Alpers
Department of Psychology, Humboldt University, Berlin, Germany.
T
T
Fydrich
Department of Psychology, Humboldt University, Berlin, Germany.
L
L
Fehm
Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
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AL
Gerlach
Department of Psychiatry and Psychotherapy, University Hospital of Marburg, Marburg, Germany.
T
T
Kircher
Department of Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany.|Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany.|Department of Psychology, University of Hamburg, Hamburg, Germany.
T
T
Lang
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité University Medicine, Berlin, Germany.
A
A
Ströhle
Department of Psychiatry and Psychotherapy, University Hospital of Münster, Münster, Germany.
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V
Arolt
Department of Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany.
H-U
HU
Wittchen
Neuroimaging Center (NIC) und Deutsches Resilienz-Zentrum (DRZ), Johannes Gutenberg University Medical Center, Mainz, Germany.
R
R
Kalisch
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
C
C
Büchel
Department of Psychology, University of Greifswald, Greifswald, Germany.
A
A
Hamm
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
M M
MM
Nöthen
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
M
M
Romanos
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
K
K
Domschke
Department of Psychology, and Center of Mental Health, University of Würzburg, Würzburg, Germany.
P
P
Pauli
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
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Reif
D000328:Adult; D000379:Agoraphobia / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D001007:Anxiety / Q000150:complications; D001008:Anxiety Disorders / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000502:physiology; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology; D005239:Fear / Q000502:physiology / Q000523:psychology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D016584:Panic Disorder / Q000235:genetics; D018009:Receptors, Glycine / Q000235:genetics* / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics
C114561:GLRB protein, human; D018009:Receptors, Glycine