DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli

DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli

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J Psychiatry Neurosci 2015;40(5):296-305

Thomas Frodl, MD; Moshe Szyf, PhD; Angela Carballedo, MD; Victoria Ly, MSc; Sergiy Dymov, MSc; Farida Vaisheva, MD; Derek Morris, PhD; Ciara Fahey, PhD; James Meaney, MD; Michael Gill, PhD; Linda Booij, PhD


Background: The aim of the present study was to investigate the association of fMRI blood oxygen–level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD).

Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing.

Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation.

Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn.

Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Submitted July 2, 2014; Revised Oct. 4, 2014; Accepted Nov. 11, 2014; Early-released Mar. 31, 2015.

Affiliations: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James’s Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen’s University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).

Acknowledgements: The authors thank Lyndall Schumann for proofreading the manuscript. L. Booij is supported by a New Investigator Award from the Canadian Institutes of Health Research (CIHR). The DNA methylation analyses were funded by grants from the Fonds de Recherche en Santé — Québec and a Brain, Behavior Research Foundation-NARSAD Young Investigator Award awarded to L. Booij. The clinical part of the study with patient recruitment, neuroimaging and genetic data analysis was supported by Science Foundation Ireland (SFI, G20330) within a Stokes Professorship grant and by the European Union with a Marie Currie International Training Network grant (rBirth) to T. Frodl.

Competing interests: None declared.

Contributors: T. Frodl, M. Szyf, A. Carballedo, J. Meaney and L. Booij designed the study. T. Frodl, A. Carballedo, V. Ly, S. Dymov, F. Vaisheva, D. Morris, C. Fahey and M. Gill acquired the data, which T. Frodl, M. Szyf, A. Carballedo, D. Morris and L. Booij analyzed. T. Frodl and M. Szyf wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140180

Correspondence to: T. Frodl, Department of Psychiatry & Institute of Neuroscience, University Dublin, Trinity College, Dublin 2, Ireland; thomas.frodl@tcd.ie