Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits

Thomas L Kremer; Junfang Chen; Anais Buhl; Oksana Berhe; Edda Bilek; Lena S Geiger; Ren Ma; Carolin Moessnang; Markus Reichert; Iris Reinhard; Kristina Schwarz; Janina I Schweiger; Fabian Streit; Stephanie H Witt; Zhenxiang Zang; Xiaolong Zhang; Markus M Nöthen; Marcella Rietschel; Ulrich W Ebner-Priemer; Emanuel Schwarz; Andreas Meyer-Lindenberg; Urs Braun; Heike Tost

doi:10.1016/j.biopsych.2024.03.003

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits

Biol Psychiatry. 2024 Mar 7:S0006-3223(24)01141-7. doi: 10.1016/j.biopsych.2024.03.003. Online ahead of print.

Authors

Thomas L Kremer¹, Junfang Chen², Anais Buhl², Oksana Berhe², Edda Bilek¹, Lena S Geiger², Ren Ma², Carolin Moessnang², Markus Reichert³, Iris Reinhard⁴, Kristina Schwarz², Janina I Schweiger¹, Fabian Streit⁵, Stephanie H Witt⁶, Zhenxiang Zang², Xiaolong Zhang², Markus M Nöthen⁷, Marcella Rietschel⁶, Ulrich W Ebner-Priemer⁸, Emanuel Schwarz⁹, Andreas Meyer-Lindenberg¹, Urs Braun⁹, Heike Tost¹⁰

Affiliations

¹ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany.
² Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mental mHealth Lab, Chair of Applied Psychology, Institute of Sports and Sports Science, Karlsruhe Institute of Technology, Karlsruhe, Germany; Department of eHealth and Sports Analytics, Ruhr University Bochum, Bochum, Germany.
⁴ Department of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵ DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany; Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁶ DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁸ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany; Mental mHealth Lab, Chair of Applied Psychology, Institute of Sports and Sports Science, Karlsruhe Institute of Technology, Karlsruhe, Germany.
⁹ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany; Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁰ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DZPG (German Center for Mental Health), partner site Mannheim/Heidelberg/Ulm, Germany. Electronic address: heike.tost@zi-mannheim.de.

PMID: 38460581
DOI: 10.1016/j.biopsych.2024.03.003

Abstract

Background: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity.

Methods: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals.

Results: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life.

Conclusions: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Keywords: Ambulatory assessment; Epigenetics; FKBP5; Prefrontal cortex; Stress.