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

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 -