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An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation—DNA methyltransferases (DNMTs)—has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

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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 [multicenter trial “Mechanisms of CBT-treatment effects in patients with panic disorder and panic disorder with agoraphobia: The role of interoceptive exposure and fear augmentation (MCBT-PDAS)”] studies. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—project number 44541416—TRR 58 “Fear, Anxiety, Anxiety Disorders”, project Z02 to JD, AR, MR and PP, B01 to PP, B06 to AR, B07 to TL, and C02 to KD and JD. RK was supported by the DFG grant KA1623/3-1. 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), A. L. 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: G. W. Alpers (Würzburg), T. Fydrich and L. Fehm (Berlin-Adlershof) and T. Lang (Bremen). Acknowledgements and staff members by site: Greifswald (coordinating site for Psychophysiology): Christiane Pané-Farré, Jan Richter, Susan Richter, Matthias von Rad; Berlin-Charité (coordinating Center for Experimental Pharmacology): Harald Bruhn, Anja Siegmund, Meline Stoy, André Wittmann; Berlin-Adlershof: Irene Schulz; Münster (Overall MAC Program Coordination, Genetics and Functional Neuroimaging): Andreas Behnken, Katharina Domschke, Adrianna Ewert, Carsten Konrad, Bettina Pfleiderer, Christina Uhlmann, Peter Zwanzger; Münster (coordinating site for psychophysiology and subtyping): Judith Eidecker, Swantje Koller, Fred Rist, Anna Vossbeck-Elsebusch; Marburg/Aachen (coordinating center for functional neuroimaging): Barbara Drüke, Sonja Eskens, Thomas Forkmann, Siegfried Gauggel, Susan Gruber, Andreas Jansen, Thilo Kellermann, Isabelle Reinhardt, Nina Vercamer-Fabri; Dresden (coordinating site for data collection, analysis, and the RCT): Franziska Einsle, Christine Froehlich, Andrew T. Gloster, Christina Hauke, Simone Heinze, Michael Hoefler, Ulrike Lueken, Peter Neudeck, Stephanie Preiß, Dorte Westphal; Würzburg Psychiatry Department (coordinating center for genetics): Andreas Reif, Caro Gagel; Würzburg Psychology Department: Julia Duerner, Hedwig Eisenbarth, Antje B. M. Gerdes, Harald Krebs, Paul Pauli, Silvia Schad, Nina Steinhäuser; Bremen: Veronika Bamann, Sylvia Helbig-Lang, Anne Kordt, Pia Ley, Franz Petermann, Eva-Maria Schroeder. Additional support was provided by the coordinating center for clinical studies in Dresden (KKS Dresden): Xina Graehlert and Marko Käppler. The MCBT-PDAS study was funded by the German Federal Ministry of Education and Research (BMBF, 01GV0614) as part of the larger BMBF Psychotherapy Research Funding Initiative Improving the Treatment of Panic Disorder. Principal investigators (PI) with respective areas of competence of the MCBT-PDAS are Alfons Hamm (Greifswald: PI Psychophysiology); Thomas Lang (Bremen: Study Director for the Randomized Clinical Trial (RCT) and Manual Development); Alexander L. Gerlach (Münster: PI Panic subtypes); Georg W. Alpers (Mannheim: PI Ambulatory assessment); Christiane Pané-Farré (Greifswald: PI Psychophysiology and Panic Disorder); Tilo Kircher (Marburg: PI for functional neuroimaging), and Jürgen Deckert (Würzburg: PI for Genetics). Additional site directors in the RCT component of the program are Winfried Rief (Marburg), and Paul Pauli (Würzburg). Centers of the Research Network: Volker Arolt (Münster: Overall Network Coordination), Hans-Ulrich Wittchen (Dresden), Andreas Ströhle (Berlin). Data Access and Responsibility: All principle investigators take responsibility for the integrity of the respective study data and their components. All authors and co-authors had full access to all study data. Data analysis and manuscript preparation were completed by the authors and co-authors of this article, who take responsibility for its accuracy and content. Acknowledgements and staff members by site: Bremen (coordinating center for the multicenter trial): Veronika Bamann, Sandra Cammin, Sarah Czilwik, Kira Geisler, Sylvia Helbig-Lang, Kirsten Helmes, Anne Kordt, Tanja Leonhard, Mila Plett-Perelshteyn, Christian Soltau, Juliane Sülz, Maxie von Auer; Greifswald (coordinating site for psychophysiology): Anett Hoffmann, Jan Richter; Mannheim (coordinating center for ambulatory assessment): Christoph Biwer, Elisabeth Borgmann, Antje Gerdes, Otto Martin, Kristina Steinbach, Bettina Stemmler, Andrew White; Marburg (coordinating center for functional neuroimaging): Tobias Fehlinger, Andreas Jansen, Nikita Jegan, Carsten Konrad, Marion Mickeler, Silke Rusch, Katrin Schlötterer, Benjamin Straube, Mareike Stumpenhorst, Katrin Wambach, Yunbo Yang; Münster (coordinating site for panic subtypes): Susanne Kettler, Anna Vossbeck-Elsebusch; Würzburg Psychiatry Department (coordinating center for genetics): Carola Gagel, Andreas Reif, Heike Weber; Würzburg Psychology Department: Almut Friedl-Huber, Harald Krebs, Caroline Ott, Nina Steinhäuser; Additional support was provided by the coordinating center for clinical studies in Dresden (KKS Dresden): Marko Käppler. The study was registered with the NCT01323556. T. Lonsdorf and D. Schümann are credited for CRC-TRR-58 Mega Study wave 1 and 2 recruitement at Hamburg and C. Gagel, N. Döring and I. Reck for excellent technical assistance at Würzburg.

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Authors and Affiliations

  1. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel Platz 1, 97080, Würzburg, Germany

    Ann-Cathrine Berking, Christian Baumann, Jürgen Deckert & Heike Weber

  2. Department of Human Genetics, Hannover Medical School, Hannover, Germany

    Ann-Cathrine Berking

  3. Department of Psychiatry and Psychotherapy, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany

    Christiane Thiel, Miriam A. Schiele & Katharina Domschke

  4. Department of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), Center of Mental Health, University of Würzburg, Würzburg, Germany

    Christian Baumann & Paul Pauli

  5. Neuroimaging Center (NIC), Johannes Gutenberg University Medical Center, Mainz, Germany

    Raffael Kalisch

  6. Leibniz Institute for Resilience Research, Mainz, Germany

    Raffael Kalisch

  7. Catholic University of Applied Science Münster, Münster, Germany

    Raffael Kalisch & Swantje Notzen

  8. Department of Psychiatry and Psychotherapy, District Hospital Gabersee, Wasserburg am Inn, Germany

    Peter Zwanzger

  9. Institute of Psychology, University of Greifswald, Greifswald, Germany

    Christiane A. Pané-Farré & Alfons Hamm

  10. Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany

    Georg W. Alpers

  11. Institute of Psychology, Humboldt University, Berlin, Germany

    Thomas Fydrich & Lydia Fehm

  12. Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany

    Alexander L. Gerlach

  13. Department of Psychiatry and Psychotherapy, University Hospital of Marburg, Marburg, Germany

    Benjamin Straube & Tilo Kircher

  14. Institute of Psychology, Philipps University Marburg, Marburg, Germany

    Christiane A. Pané-Farré & Winfried Rief

  15. Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Charité Mitte, Berlin, Germany

    Jens Plag & Andreas Ströhle

  16. Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany

    Thomas Lang

  17. Department of Psychology and Methods, Jacobs University Bremen, Bremen, Germany

    Thomas Lang

  18. Institute of Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany

    Hans-Ulrich Wittchen

  19. Department of Psychiatry, University of Münster, Münster, Germany

    Swantje Notzen, Peter Zwanzger & Volker Arolt

  20. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany

    Marcel Romanos

  21. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany

    Andreas Reif

  22. Department of Psychiatry and Psychotherapy LMU, Munich, Germany

    Peter Zwanzger & Hans-Ulrich Wittchen

  23. Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Katharina Domschke

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  1. Ann-Cathrine Berking
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  2. Christiane Thiel
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  3. Miriam A. Schiele
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  4. Christian Baumann
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  5. Raffael Kalisch
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  6. Swantje Notzen
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  7. Peter Zwanzger
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  8. Christiane A. Pané-Farré
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  9. Alfons Hamm
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  10. Georg W. Alpers
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  11. Thomas Fydrich
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  12. Lydia Fehm
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  13. Alexander L. Gerlach
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  14. Benjamin Straube
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  15. Tilo Kircher
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  16. Winfried Rief
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  17. Jens Plag
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  18. Andreas Ströhle
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  19. Thomas Lang
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  20. Hans-Ulrich Wittchen
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  21. Volker Arolt
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  22. Marcel Romanos
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  23. Paul Pauli
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  24. Andreas Reif
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  25. Jürgen Deckert
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  26. Katharina Domschke
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  27. Heike Weber
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Correspondence to Heike Weber.

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Over the last 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. K. Domschke is a member of the Janssen Pharmaceuticals, Inc. Steering Committee Neurosciences. R. Kalisch receives advisory honoraria from JoyVentures, Herzlia, Israel. T. Kircher received fees for educational programs from Janssen, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb, Pfizer and Astra-Zeneca. P. Pauli is a shareholder 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 AstraZeneca, 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 EssexPharma 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 other authors declare no conflict of interest.

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Berking, AC., Thiel, C., Schiele, M.A. et al. An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes. J Neural Transm 127, 1527–1537 (2020). https://doi.org/10.1007/s00702-020-02206-x

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