Deckert, J., Weber, H., Villmann, C., Lonsdorf, T. B., Richter, J., Andreatta, M., Arias-Vasquez, A., Hommers, L., Kent, L., Schartner, C., Cichon, S., Wolf, C., Schaefer, N., von Collenberg, C. R., Wachter, B., Blum, R., Schuemann, 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., Muehlberger, A., Alpers, G., Fydrich, T., Fehm, L., Gerlach, A. L., Kircher, T., Lang, T., Stroehle, A., Arolt, V., Wittchen, H-U, Kalisch, R., Buechel, C., Hamm, A., Noethen, M. M., Romanos, M., Domschke, K., 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. Mol. Psychiatr., 22 (10). S. 1431 - 1440. LONDON: NATURE PUBLISHING GROUP. ISSN 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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Deckert, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villmann, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lonsdorf, T. B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andreatta, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arias-Vasquez, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hommers, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kent, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schartner, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cichon, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Collenberg, C. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachter, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blum, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuemann, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scharfenort, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forstner, A. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiele, M. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Notzon, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwanzger, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janzing, J. G. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galesloot, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiemeney, L. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gajewska, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glotzbach-Schoon, E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muehlberger, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alpers, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fydrich, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fehm, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerlach, A. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kircher, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroehle, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arolt, V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittchen, H-UUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalisch, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buechel, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamm, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, M. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romanos, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domschke, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauli, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-216883
DOI: 10.1038/mp.2017.2
Journal or Publication Title: Mol. Psychiatr.
Volume: 22
Number: 10
Page Range: S. 1431 - 1440
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5578
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; GLYCINE RECEPTOR; ELEMENT INSERTION; MONOAMINE-OXIDASE; SPASTIC MOUSE; GENE; ANXIETY; POLYMORPHISM; METAANALYSIS; LOCUSMultiple languages
Biochemistry & Molecular Biology; Neurosciences; PsychiatryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21688

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