GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder
| Autor: | Hans-Ulrich Wittchen, Peter Zwanzger, Alejandro Arias-Vasquez, Johannes Schumacher, Andreas Mühlberger, Andreas J. Forstner, Tina B. Lonsdorf, Sven Cichon, Miriam A. Schiele, Georg W. Alpers, Tilo Kircher, Christian Baumann, Marcel Romanos, Paul Pauli, Christoph Schartner, Agnieszka Gajewska, Volker Arolt, Jürgen Deckert, Swantje Notzon, Raffael Kalisch, Christian Büchel, Marta Andreatta, Thomas Fydrich, Leif Hommers, Lydia Fehm, Heike Weber, Lambertus A. Kiemeney, Katharina Domschke, Dirk Schümann, Alexander L. Gerlach, Jan Richter, Robert Scharfenort, Robert Blum, Natascha Schaefer, C. R. von Collenberg, Christiane Wolf, Andreas Reif, Alfons O. Hamm, Joost G. E. Janzing, Thomas Lang, Evelyn Glotzbach-Schoon, Andreas Ströhle, Lindsey Kent, M. M. Nöthen, Britta Wachter, Tessel E. Galesloot, Carmen Villmann |
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| Přispěvatelé: | University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Startle response Reflex Startle QH301 Biology Genome-wide association study Gene mutation Anxiety 0302 clinical medicine Cognition Receptors Glycine Gene Frequency Germany GWAS Hyperekplexia Genetics Panic disorder medicine.diagnostic_test Startle Brain Fear GLRB Anxiety Disorders Psychiatry and Mental health Schizophrenia Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] Panic Disorder Female medicine.symptom Psychology BDC RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry Clinical psychology Adult Genotype NDAS QH426 Genetics 03 medical and health sciences Cellular and Molecular Neuroscience QH301 Fear network Spastic mouse medicine Humans Genetic Predisposition to Disease Molecular Biology QH426 Agoraphobia Alleles Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Other Research Radboud Institute for Health Sciences [Radboudumc 0] medicine.disease Startle reaction 030104 developmental biology MCP Case-Control Studies Mutation RC0321 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Molecular Psychiatry, 22, 10, pp. 1431-1439 Molecular Psychiatry, 22, 1431-1439 |
| ISSN: | 1476-5578 1359-4184 |
| Popis: | Contains fulltext : 177350.pdf (Publisher’s version ) (Closed access) 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 (Ncombined =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. |
| Databáze: | OpenAIRE |
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