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

Deckert, J. and Weber, H. and Villmann, C. and Lonsdorf, T. B. and Richter, J. and Andreatta, M. and Arias-Vasquez, A. and Hommers, L. and Kent, L. and Schartner, C. and Cichon, S. and Wolf, C. and Schaefer, N. and von Collenberg, C. R. and Wachter, B. and Blum, R. and Schuemann, D. and Scharfenort, R. and Schumacher, J. and Forstner, A. J. and Baumann, C. and Schiele, M. A. and Notzon, S. and Zwanzger, P. and Janzing, J. G. E. and Galesloot, T. and Kiemeney, L. A. and Gajewska, A. and Glotzbach-Schoon, E. and Muehlberger, A. and Alpers, G. and Fydrich, T. and Fehm, L. and Gerlach, A. L. and Kircher, T. and Lang, T. and Stroehle, A. and Arolt, V. and Wittchen, H-U and Kalisch, R. and Buechel, C. and Hamm, A. and Noethen, M. M. and Romanos, M. and Domschke, K. and Pauli, P. and Reif, A. (2017) GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder. MOLECULAR PSYCHIATRY, 22 (10). pp. 1431-1439. ISSN 1359-4184, 1476-5578

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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 x 10(-8); rs191260602, P = 3.9 x 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 (N-combined = 1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P = 3.8 x 10(-4)) and rs7688285 (P = 7.6 x 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.

Item Type: Article
Uncontrolled Keywords: GENOME-WIDE ASSOCIATION; GLYCINE RECEPTOR; ELEMENT INSERTION; MONOAMINE-OXIDASE; SPASTIC MOUSE; GENE; ANXIETY; POLYMORPHISM; METAANALYSIS; LOCUS;
Subjects: 100 Philosophy & psychology > 150 Psychology
Divisions: Psychology and Pedagogy > Institut für Psychologie > Lehrstuhl für Psychologie III (Biologische, Klinische und Rehabilitationspsychologie) - Prof. Dr. Klaus W. Lange
Depositing User: Dr. Gernot Deinzer
Date Deposited: 14 Dec 2018 13:19
Last Modified: 01 Mar 2019 08:30
URI: https://pred.uni-regensburg.de/id/eprint/2127

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