Abstract

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.

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Acknowledgements

We would like to thank Ahmad Hariri for providing the fMRI-paradigm and our reviewers for their very helpful comments that improved our manuscript substantially.

Author information

Author notes

    • Ilona Schneider
    •  & Harald Kugel

    These first authors contributed equally to this work.

    • Udo Dannlowski
    •  & Christa Hohoff

    These senior authors contributed equally to this work.

Affiliations

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

    • Ilona Schneider
    • , Ronny Redlich
    • , Dominik Grotegerd
    • , Christian Bürger
    • , Nils Opel
    • , Katharina Dohm
    • , Dario Zaremba
    • , Susanne Meinert
    • , Nina Schröder
    • , Anna Milena Straßburg
    • , Kathrin Schwarte
    • , Christiane Schettler
    • , Oliver Ambrée
    • , Katharina Domschke
    • , Volker Arolt
    • , Weiqi Zhang
    • , Udo Dannlowski
    •  & Christa Hohoff
  2. Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Münster, Germany

    • Ilona Schneider
    • , Volker Arolt
    • , Weiqi Zhang
    •  & Udo Dannlowski
  3. Department of Clinical Radiology, University of Münster, Münster, Germany

    • Harald Kugel
    •  & Walter Heindel
  4. Department of Psychology, University of Münster, Münster, Germany

    • Paul-Christian Bürkner
  5. Department of Behavioural Biology, University of Osnabrück, Osnabrück, Germany

    • Oliver Ambrée
  6. Department of Pediatrics, University of Münster, Münster, Germany

    • Stephan Rust
  7. Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    • Katharina Domschke
  8. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia

    • Bernhard T Baune

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https://doi.org/10.1038/npp.2017.273

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)

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