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

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Jürgen Deckert, Heike Weber, Carmen Villmann, Tina B. Lonsdorf, Jan Richter, Marta Andreatta, Alejandro Arias-Vasquez, Leif Hommers, Lindsey Kent, Christoph Schartner, Sven Cichon, Christian Wolf, Natascha Schaefer, Cora R. von Collenberg, Britta Wachter, Robert Blum, Dirk Schümann, Robert Scharfenort, Johannes Schumacher, Andreas J. Forstner & 27 others Christian Baumann, Miriam A. Schiele, Swantje Notzon, Peter Zwanzger, Joost G.E. Janzing, Tessel Galesloot, Lambertus A. Kiemeney, Agnes Gajewska, Evelyn Glotzbach-Schoon, Andreas Mühlberger, Georg Alpers, Thomas Fydrich, Lydia Fehm, Alexander L. Gerlach, Tilo Kircher, Thomas Lang, Andreas Ströhle, Volker Arolt, Hans-Ulrich Wittchen, Raffael Kalisch, Christian Büchel, Alfons Hamm, Markus M. Nöthen, Marcel Romanos, Katharina Domschke, Pauli Pauli, Andreas Reif

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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 1,370 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=3.3x10-8; rs191260602, p=3.9x10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2,547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3,845) and a case control sample with the categorical phenotype PD/AG (Ncombined =1,012) obtaining highly significant p-values also for GLRB single nucleotide variants rs17035816 (p=3.8x10-4) and rs7688285 (p=7.6x10-5). 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 withthe 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, though functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.
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Original languageEnglish
Pages (from-to)1431-1439
Number of pages9
JournalMolecular Psychiatry
Issue number22
Early online date7 Feb 2017
DOIs
Publication statusPublished - 2017

    Research areas

  • Agoraphobia, GWAS, GLRB, Startle, Fear network, Spastic mouse, Panic disorder

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