DNA methylation (DNAM) changes in the FKBP5 gene have been identified as a potential molecular mechanism explaining how environmental adversity may confer long-term health risks. However, the neurobiological correlates of epigenetic signatures in FKBP5 have only recently been explored in human brain imaging research. The present study aims to investigate associations of FKBP5 DNAM and functional network architecture during an implicit emotion regulation task (N = 74 healthy individuals). For this, we applied a data-driven multi-voxel pattern analysis (MVPA) to identify regions, where connectivity values vary as a function of FKBP5 DNAM, which then served as seed regions for functional network architecture analyses. Blood-derived DNA samples were obtained to analyze quantitative DNAM at three CpGs sites in intron 7 of the FKBP5 gene using bisulfite pyrosequencing. MPVA revealed a cluster within the right rostral ACC and the paracingulate ACCs, where connectivity patterns were strongly related to FKBP5 DNAM. Using this cluster as seed region for connectivity analyses, we further identified a functional network, including prefrontal, subcortical, insular, and thalamic regions, where connectivity patterns positively correlated with FKBP5 DNAM. A subsequent behavioral domain analyses to determine the functional specialization of this network revealed highest effect sizes for subdomains that represent affective and cognitive processes. Together, these findings suggest that FKBP5 demethylation predicts a widespread functional disruption in a brain network centrally implicated in emotion regulation and cognition, which may in turn convey increased disease susceptibility.
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Funding: This research was supported by the intramural research funding of the TU-Dresden to N.A. and M.M. M.M. R.M. and M.N.S acknowledged support by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) grants CRC (SFB) 940/1 and/or CRC (SFB) 940/2.
We would like to thank Matthis Wankerl and Janin Keitel for assisting in participant recruitment. We further thank Prof. Martin Reuter for carrying out the rs1360780 genotyping in his lab.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of the Technische Universität Dresden [EK: 152052012]. All participants were carefully introduced to the study protocol and filled in a consent form prior to testing.
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Muehlhan, M., Miller, R., Strehle, J. et al. FKBP5 methylation predicts functional network architecture of the rostral anterior cingulate cortex. Brain Struct Funct 225, 33–43 (2020). https://doi.org/10.1007/s00429-019-01980-z
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