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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GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder. / 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; 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.
in: MOL PSYCHIATR, Jahrgang 22, Nr. 10, 10.2017, S. 1431-1439.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder
AU - Deckert, J
AU - Weber, H
AU - Villmann, C
AU - Lonsdorf, T B
AU - Richter, J
AU - Andreatta, M
AU - Arias-Vasquez, A
AU - Hommers, L
AU - Kent, L
AU - Schartner, C
AU - Cichon, S
AU - Wolf, C
AU - Schaefer, N
AU - von Collenberg, C R
AU - Wachter, B
AU - Blum, R
AU - Schümann, D
AU - Scharfenort, R
AU - Schumacher, J
AU - Forstner, A J
AU - Baumann, C
AU - Schiele, M A
AU - Notzon, S
AU - Zwanzger, P
AU - Janzing, J G E
AU - Galesloot, T
AU - Kiemeney, L A
AU - Gajewska, A
AU - Glotzbach-Schoon, E
AU - Mühlberger, A
AU - Alpers, G
AU - Fydrich, T
AU - Fehm, L
AU - Gerlach, A L
AU - Kircher, T
AU - Lang, T
AU - Ströhle, A
AU - Arolt, V
AU - Wittchen, H-U
AU - Kalisch, R
AU - Büchel, C
AU - Hamm, A
AU - Nöthen, M M
AU - Romanos, M
AU - Domschke, K
AU - Pauli, P
AU - Reif, A
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Adult
KW - Agoraphobia
KW - Alleles
KW - Anxiety
KW - Anxiety Disorders
KW - Brain
KW - Case-Control Studies
KW - Cognition
KW - Fear
KW - Female
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotype
KW - Germany
KW - Humans
KW - Male
KW - Mutation
KW - Panic Disorder
KW - Receptors, Glycine
KW - Reflex, Startle
KW - Journal Article
U2 - 10.1038/mp.2017.2
DO - 10.1038/mp.2017.2
M3 - SCORING: Journal article
C2 - 28167838
VL - 22
SP - 1431
EP - 1439
JO - MOL PSYCHIATR
JF - MOL PSYCHIATR
SN - 1359-4184
IS - 10
ER -