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RESEARCH PRODUCT
GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.
Hans-ulrich WittchenPeter ZwanzgerAlejandro Arias-vasquezJohannes SchumacherJohannes SchumacherAndreas MühlbergerAndreas J. ForstnerAndreas J. ForstnerTina B. LonsdorfSven CichonMiriam A. SchieleGeorg W. AlpersTilo KircherChristian BaumannMarcel RomanosPaul PauliChristoph SchartnerAgnieszka GajewskaVolker AroltJürgen DeckertSwantje NotzonRaffael KalischChristian BüchelMarta AndreattaThomas FydrichLeif HommersLydia FehmHeike WeberLambertus A. KiemeneyKatharina DomschkeDirk SchümannAlexander L. GerlachJan RichterRobert ScharfenortRobert BlumNatascha SchaeferC. R. Von CollenbergChristiane WolfAndreas ReifAlfons O. HammJoost G. E. JanzingThomas LangThomas LangThomas LangEvelyn Glotzbach-schoonAndreas StröhleLindsey KentM. M. NöthenM. M. NöthenBritta WachterTessel E. GaleslootCarmen Villmannsubject
0301 basic medicineMaleStartle responseReflex StartleQH301 BiologyGenome-wide association studyGene mutationAnxiety0302 clinical medicineCognitionReceptors GlycineGene FrequencyGermanyGWASHyperekplexiaGeneticsPanic disordermedicine.diagnostic_testStartleBrainFearGLRBAnxiety DisordersPsychiatry and Mental healthSchizophreniaUrological cancers Radboud Institute for Health Sciences [Radboudumc 15]Panic DisorderFemalemedicine.symptomPsychologyBDCRC0321 Neuroscience. Biological psychiatry. NeuropsychiatryClinical psychologyAdultGenotypeNDASQH426 Genetics03 medical and health sciencesCellular and Molecular NeuroscienceQH301Fear networkSpastic mousemedicineHumansGenetic Predisposition to DiseaseMolecular BiologyQH426AgoraphobiaAllelesNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Panic disorderOther Research Radboud Institute for Health Sciences [Radboudumc 0]medicine.diseaseStartle reaction030104 developmental biologyMCPCase-Control StudiesMutationRC0321030217 neurology & neurosurgeryAgoraphobiaGenome-Wide Association Studydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-01-01 | Molecular psychiatry |