Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors

Vanja Vukojevic; Iris-T Kolassa; Matthias Fastenrath; Leo Gschwind; Klara Spalek; Annette Milnik; Angela Heck; Christian Vogler; Sarah Wilker; Philippe Demougin; Fabian Peter; Erika Atucha; Attila Stetak; Benno Roozendaal; Thomas Elbert; Andreas Papassotiropoulos; Dominique J-F de Quervain

doi:10.1523/JNEUROSCI.1526-14.2014

Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors

J Neurosci. 2014 Jul 30;34(31):10274-84. doi: 10.1523/JNEUROSCI.1526-14.2014.

Authors

Vanja Vukojevic¹, Iris-T Kolassa², Matthias Fastenrath³, Leo Gschwind³, Klara Spalek³, Annette Milnik⁴, Angela Heck⁵, Christian Vogler⁵, Sarah Wilker², Philippe Demougin⁶, Fabian Peter⁶, Erika Atucha⁷, Attila Stetak⁸, Benno Roozendaal⁷, Thomas Elbert⁹, Andreas Papassotiropoulos¹⁰, Dominique J-F de Quervain¹¹

Affiliations

¹ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Department Biozentrum, Life Sciences Training Facility, University of Basel, CH-4056 Basel, Switzerland, vanja.vukojevic@unibas.ch dominique.dequervain@unibas.ch.
² Clinical & Biological Psychology, Institute of Psychology and Education, University of Ulm, D-89069 Ulm, Germany.
³ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Department of Psychology, Division of Cognitive Neuroscience, University of Basel, CH-4055 Basel, Switzerland.
⁴ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland.
⁵ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland, Transfacultary Research Platform, University of Basel, CH-4055 Basel, Switzerland.
⁶ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Department Biozentrum, Life Sciences Training Facility, University of Basel, CH-4056 Basel, Switzerland.
⁷ Department of Cognitive Neuroscience and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, Netherlands, and.
⁸ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Department Biozentrum, Life Sciences Training Facility, University of Basel, CH-4056 Basel, Switzerland, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland.
⁹ Clinical Psychology and Neuropsychology, University of Konstanz, D-78464 Konstanz, Germany.
¹⁰ Department of Psychology, Division of Molecular Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Department Biozentrum, Life Sciences Training Facility, University of Basel, CH-4056 Basel, Switzerland, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland, Transfacultary Research Platform, University of Basel, CH-4055 Basel, Switzerland.
¹¹ Department of Psychology, Division of Cognitive Neuroscience, University of Basel, CH-4055 Basel, Switzerland, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland, Transfacultary Research Platform, University of Basel, CH-4055 Basel, Switzerland, vanja.vukojevic@unibas.ch dominique.dequervain@unibas.ch.

Abstract

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

Keywords: DNA methylation; GR; PTSD; memory.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Brain / blood supply
Brain / pathology
DNA Methylation
Epigenesis, Genetic / genetics*
Female
Genetic Association Studies
Genocide / psychology*
Genotype
Humans
Image Processing, Computer-Assisted
Male
Memory*
Neuropsychological Tests
Oxygen / blood
Promoter Regions, Genetic / genetics
Psychiatric Status Rating Scales
Receptors, Glucocorticoid / genetics*
Risk
Rwanda
Stress Disorders, Post-Traumatic* / genetics
Stress Disorders, Post-Traumatic* / pathology
Stress Disorders, Post-Traumatic* / psychology
Survivors / psychology*
Switzerland
Young Adult

Substances

NR3C1 protein, human
Receptors, Glucocorticoid
Oxygen