Journal Article

FZJ-2017-02049

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

Deckert, J. (Corresponding author) ; Weber, H. ; Villmann, C. ; Lonsdorf, T. B. ; Richter, J. ; Andreatta, M. ; Arias-Vasquez, A. ; Hommers, L. ; Kent, L. ; Schartner, C. ; Cichon, S.FZJ* ; Wolf, C. ; Schaefer, N. ; von Collenberg, C. R. ; Wachter, B. ; Blum, R. ; Schümann, D. ; Scharfenort, R. ; Schumacher, J. ; Forstner, A. J. ; Baumann, C. ; Schiele, M. A. ; Notzon, S. ; Zwanzger, P. ; Janzing, J. G. E. ; Galesloot, T. ; Kiemeney, L. A. ; Gajewska, A. ; Glotzbach-Schoon, E. ; Mühlberger, A. ; Alpers, G. ; Fydrich, T. ; Fehm, L. ; Gerlach, A. L. ; Kircher, T. ; Lang, T. ; Ströhle, A. ; Arolt, V. ; Wittchen, H.-U. ; Kalisch, R. ; Büchel, C. ; Hamm, A. ; Nöthen, M. M. ; Romanos, M. ; Domschke, K. ; Pauli, P. ; Reif, A.

2017
Macmillan London

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Please use a persistent id in citations: doi:10.1038/mp.2017.2

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.

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Contributing Institute(s):

1. Strukturelle und funktionelle Organisation des Gehirns (INM-1)

Research Program(s):

1. 571 - Connectivity and Activity (POF3-571) (POF3-571)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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