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 × 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.

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Acknowledgements

We are grateful to all individuals who participated in this study either as part of the CRC-TRR-58 Mega study wave 1 and 2 or the German PanicNet wave 1 (multicenter trial 'Mechanisms of Action in CBT (MAC)') or wave 2 studies. The study was supported by the DFG CRC-TRR-58 grants Z02 to JD, AR, MR and PP, A08 to RB, B01 to AM and PP, B03 to CB, B06 to AR and CB, B07 to TL, and C02 to KD and JD. RK was supported by the DFG grant KA1623/3-1 and MA by the RTG1253. The MAC study was funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The principal investigators (PIs) of the centers with respective areas of responsibility in the MAC study are: V Arolt (Münster: Overall MAC Program Coordination), H-U Wittchen (Dresden: PI for the Randomized Clinical Trial and Manual Development), A Hamm (Greifswald: PI for Psychophysiology), AL Gerlach (Münster: PI for Psychophysiology and Panic subtypes), A Ströhle (Berlin: PI for Experimental Pharmacology), T Kircher (Marburg: PI for functional neuroimaging) and J Deckert (Würzburg: PI for Genetics). Additional site directors in the randomized controlled trial component of the program are as follows: GW Alpers (Würzburg), T Fydrich and L Fehm (Berlin-Adlershof) and T Lang (Bremen). Further support was obtained from the IZKF-Würzburg Z-6 to HW and the IZKF-Würzburg N-258 to LH. The Nijmegen Biomedical Study is a population-based survey conducted at the Department for Health Evidence and the Department of Laboratory Medicine of the Radboud university medical center. Principal investigators of the Nijmegen Biomedical Study are LALM Kiemeney, ALM Verbeek, DWSwinkels and B Franke. The Genome of the Netherlands Project (http://www.bbmriwiki.nl/wiki/Impute2Pipeline), and specifically Freerk van Dijk and Morris Swertz, are thanked for imputation of the genotype data with 1000 genomes phase 1 integrated version 3 and GoNL4. We credit the MRC Sudden Death Brain and Tissue Bank, Edinburgh, Scotland for providing brain tissue samples examined in this study. T Töpner, I Reck, N Steigerwald, C Gagel and J Auer are credited for excellent technical assistance.

Author information

Author notes

    • J Deckert
    •  & H Weber

    These authors share first authorship.

    • P Pauli
    •  & A Reif

    These authors share last authorship.

Affiliations

  1. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

    • J Deckert
    • , H Weber
    • , L Hommers
    • , C Schartner
    • , C Wolf
    • , C Baumann
    • , M A Schiele
    • , A Gajewska
    •  & K Domschke
  2. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany

    • H Weber
    •  & A Reif
  3. Department of Clinical Neurobiology, University Hospital of Würzburg, Würzburg, Germany

    • C Villmann
    • , N Schaefer
    • , C R von Collenberg
    • , B Wachter
    •  & R Blum
  4. Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • T B Lonsdorf
    • , D Schümann
    • , R Scharfenort
    •  & C Büchel
  5. Department of Psychology, University of Greifswald, Greifswald, Germany

    • J Richter
    •  & A Hamm
  6. Department of Psychology, and Center of Mental Health, University of Würzburg, Würzburg, Germany

    • M Andreatta
    • , E Glotzbach-Schoon
    •  & P Pauli
  7. Donders Institute for Brain Cognition and Behavior, Departments of Psychiatry, Human Genetics and Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands

    • A Arias-Vasquez
  8. Interdisciplinary Center for Clinical Research, Department of Clinical and Molecular Neurobiology, University Hospital of Würzburg, Würzburg, Germany

    • L Hommers
  9. School of Medicine, University of St Andrews, St Andrews, UK

    • L Kent
  10. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    • S Cichon
    • , J Schumacher
    • , A J Forstner
    •  & M M Nöthen
  11. Department of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany

    • S Cichon
    • , J Schumacher
    • , A J Forstner
    •  & M M Nöthen
  12. Division of Medical Genetics, University Hospital Basel, and Department of Biomedicine, University of Basel, Basel, Switzerland

    • S Cichon
  13. Department of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

    • S Cichon
  14. Department of Psychiatry and Psychotherapy, University Hospital of Münster, Münster, Germany

    • S Notzon
    • , P Zwanzger
    •  & V Arolt
  15. Department of Psychiatry and Psychotherapy, District Hospital Gabersee, Wasserburg, Germany

    • P Zwanzger
  16. Department of Psychiatry Radboud University Medical Center, Nijmegen, The Netherlands

    • J G E Janzing
  17. Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmwegen, The Netherlands

    • T Galesloot
    •  & L A Kiemeney
  18. Department of Psychology, University of Regensburg, Regensburg, Germany

    • A Mühlberger
  19. Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany

    • G Alpers
  20. Department of Psychology, Humboldt University, Berlin, Germany

    • T Fydrich
    •  & L Fehm
  21. Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany

    • A L Gerlach
  22. Department of Psychiatry and Psychotherapy, University Hospital of Marburg, Marburg, Germany

    • T Kircher
  23. Department of Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany

    • T Lang
    •  & H-U Wittchen
  24. Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany

    • T Lang
  25. Department of Psychology, University of Hamburg, Hamburg, Germany

    • T Lang
  26. Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité University Medicine, Berlin, Germany

    • A Ströhle
  27. Neuroimaging Center (NIC) und Deutsches Resilienz-Zentrum (DRZ), Johannes Gutenberg University Medical Center, Mainz, Germany

    • R Kalisch
  28. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

    • M Romanos

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Competing interests

Over the last 3 years, V Arolt has been a member of the advisory boards and/or gave presentations for the following companies: Astra-Zeneca, Eli Lilly, Janssen-Organon, Lundbeck, Otsuka, Servier and Trommsdorff. He also received sponsorships for symposia and educational activities from Astra-Zeneca, Jansen-Organon, Lundbeck and Servier. C Büchel received speaker's honoraria from Janssen. K Domschke has received a honorarium for a scientific talk from Hexal. T Kircher received fees for educational programs from Janssen, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb, Pfizer and Astra-Zeneca. P Pauli and A Mühlberger are shareholders of a commercial company that develops virtual environment research systems for empirical studies in the field of psychology, psychiatry and psychotherapy. A Ströhle received research funding from Lundbeck, and speaker honoraria from Astra-Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth and UCB. He was a consultant for Actelion. Educational grants were given by the Boehringer Ingelheim Fonds, the Eli Lilly International Foundation, Janssen-Cilag, Pfizer and Eli Lilly & Co. H-U Wittchen has served as a general consultant (non-product related) for Pfizer, Lundbeck, Organon, Servier and Essex Pharma and has received grant funding for his institution from Sanofi Aventis, Pfizer, Lundbeck, Novatis, Essex Pharma, Servier and Wyeth. These cooperations have no relevance to the work that is covered in the manuscript. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to J Deckert.

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https://doi.org/10.1038/mp.2017.2

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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