Skip to main content
SpringerLink
Log in

FKBP5 methylation predicts functional network architecture of the rostral anterior cingulate cortex

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Behzadi Y, Restom K, Liau J, Liu TT (2007) A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. NeuroImage 37(1):90–101

    PubMed  Google Scholar 

  • Binder EB (2017) Dissecting the molecular mechanisms of gene x environment interactions: implications for diagnosis and treatment of stress-related psychiatric disorders. Eur J Psychotraumatol 8(sup5):1412745

    PubMed  Google Scholar 

  • Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB et al (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299(11):1291–1305

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braun P, Hafner M, Nagahama Y, Hing B, McKane M, Grossbach A et al (2017) Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Eur Neuropsychopharmacol 27:S506

    Google Scholar 

  • Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I (2005) Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiat 57(8):832–840

    PubMed  Google Scholar 

  • Bromis K, Calem M, Reinders A, Williams SCR, Kempton MJ (2018) Meta-analysis of 89 structural MRI studies in posttraumatic stress disorder and comparison with major depressive disorder. Am J Psychiatry 175:989–998

    PubMed  PubMed Central  Google Scholar 

  • Bryant RA, Felmingham KL, Liddell B, Das P, Malhi GS (2016) Association of FKBP5 polymorphisms and resting-state activity in a frontotemporal-parietal network. Transl Psychiatry 6(10):e925

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bush G, Luu P, Posner MI (2000) Cognitive and emotional influences in anterior cingulate cortex. Trends Cognit Sci 4(6):215–222

    CAS  Google Scholar 

  • Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5(7):374–381

    CAS  PubMed  Google Scholar 

  • Diorio D, Viau V, Meaney MJ (1993) The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 13(9):3839–3847

    CAS  PubMed  PubMed Central  Google Scholar 

  • Etkin A, Egner T, Kalisch R (2011) Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cognit Sci 15(2):85–93

    Google Scholar 

  • Etkin A, Buchel C, Gross JJ (2015) The neural bases of emotion regulation. Nat Rev Neurosci 16(11):693–700

    CAS  PubMed  Google Scholar 

  • Ewald ER, Wand GS, Seifuddin F, Yang X, Tamashiro KL, Potash JB et al (2014) Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. Psychoneuroendocrinology 44:112–122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fani N, Gutman D, Tone EB, Almli L, Mercer KB, Davis J et al (2013) FKBP5 and attention bias for threat: associations with hippocampal function and shape. JAMA Psychiatry 70(4):392–400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fani N, King TZ, Reiser E, Binder EB, Jovanovic T, Bradley B et al (2014) FKBP5 genotype and structural integrity of the posterior cingulum. Neuropsychopharmacol 39(5):1206–1213

    CAS  Google Scholar 

  • Fani N, King TZ, Shin J, Srivastava A, Brewster RC, Jovanovic T et al (2016) Structural and functional connectivity in posttraumatic stress disorder: associations with FKBP5. Depress Anxiety 33(4):300–307

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fox PT, Laird AR, Fox SP, Fox PM, Uecker AM, Crank M et al (2005) BrainMap taxonomy of experimental design: description and evaluation. Hum Brain Mapp 25(1):185–198

    PubMed  PubMed Central  Google Scholar 

  • Fujii T, Ota M, Hori H, Hattori K, Teraishi T, Sasayama D et al (2014) Association between the common functional FKBP5 variant (rs1360780) and brain structure in a non-clinical population. J Psychiatr Res 58:96–101

    PubMed  Google Scholar 

  • Grabe HJ, Wittfeld K, Van der Auwera S, Janowitz D, Hegenscheid K, Habes M et al (2016) Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample. Hum Brain Mapp 37(4):1602–1613

    PubMed  PubMed Central  Google Scholar 

  • Gyurak A, Gross JJ, Etkin A (2011) Explicit and implicit emotion regulation: a dual-process framework. Cognit Emot 25(3):400–412

    Google Scholar 

  • Hair JFBW, Babin BJ, Anderson RE, Tatham RL (2006) Multivariate data analysis, 6th edn. Pearson Prentice Hall, Upper Saddle River

    Google Scholar 

  • Hall BS, Moda RN, Liston C (2015) Glucocorticoid mechanisms of functional connectivity changes in stress-related neuropsychiatric disorders. Neurobiol Stress 1:174–183

    PubMed  Google Scholar 

  • Han KM, Won E, Sim Y, Kang J, Han C, Kim YK et al (2017) Influence of FKBP5 polymorphism and DNA methylation on structural changes of the brain in major depressive disorder. Sci Rep 7:42621

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harms MB, Birn R, Provencal N, Wiechmann T, Binder EB, Giakas SW et al (2017) Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: a prospective longitudinal study. Dev Psychopathol 29(5):1895–1903

    PubMed  PubMed Central  Google Scholar 

  • Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29(8):1201–1213

    CAS  PubMed  Google Scholar 

  • Hirakawa H, Akiyoshi J, Muronaga M, Tanaka Y, Ishitobi Y, Inoue A et al (2016) FKBP5 is associated with amygdala volume in the human brain and mood state: a voxel-based morphometry (VBM) study. Int J Psychiatry Clin Pract 20(2):106–115

    CAS  PubMed  Google Scholar 

  • Holz NE, Buchmann AF, Boecker R, Blomeyer D, Baumeister S, Wolf I et al (2015) Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume. Brain Struct Funct 220(3):1355–1368

    CAS  PubMed  Google Scholar 

  • Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM et al (2013) Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 16(1):33–41

    CAS  PubMed  Google Scholar 

  • Kober H, Barrett LF, Joseph J, Bliss-Moreau E, Lindquist K, Wager TD (2008) Functional grouping and cortical-subcortical interactions in emotion: a meta-analysis of neuroimaging studies. NeuroImage 42(2):998–1031

    PubMed  Google Scholar 

  • Lancaster JL, Laird AR, Eickhoff SB, Martinez MJ, Fox PM, Fox PT (2012) Automated regional behavioral analysis for human brain images. Front Neuroinf 6:23

    Google Scholar 

  • Lanius RA, Frewen PA, Girotti M, Neufeld RW, Stevens TK, Densmore M (2007) Neural correlates of trauma script-imagery in posttraumatic stress disorder with and without comorbid major depression: a functional MRI investigation. Psychiatry Res 155(1):45–56

    PubMed  Google Scholar 

  • Lederbogen F, Kirsch P, Haddad L, Streit F, Tost H, Schuch P et al (2011) City living and urban upbringing affect neural social stress processing in humans. Nature 474(7352):498–501

    CAS  PubMed  Google Scholar 

  • LeDoux JE, Pine DS (2016) Using neuroscience to help understand fear and anxiety: a two-system framework. Am J Psychiatry 173(11):1083–1093

    PubMed  Google Scholar 

  • Lichev V, Sacher J, Ihme K, Rosenberg N, Quirin M, Lepsien J et al (2015) Automatic emotion processing as a function of trait emotional awareness: an fMRI study. Soc Cognit Affect Neurosci 10(5):680–689

    Google Scholar 

  • Lockwood PL, Wittmann MK (2018) Ventral anterior cingulate cortex and social decision-making. Neurosci Biobehav Rev 92:187–191

    PubMed  PubMed Central  Google Scholar 

  • Lundqvist D, Flykt A, Öhman A (1998) The Karolinska directed emotional faces—KDEF, CD ROM from Department of Clinical Neuroscience

  • Lupien SJ, Juster RP, Raymond C, Marin MF (2018) The effects of chronic stress on the human brain: from neurotoxicity, to vulnerability, to opportunity. Front Neuroendocrinol 49:91–105

    CAS  PubMed  Google Scholar 

  • Margraf J (1994) Entstehung und Handhabung des Mini-DIPS. Springer, Berlin

    Google Scholar 

  • McRae K, Reiman EM, Fort CL, Chen K, Lane RD (2008) Association between trait emotional awareness and dorsal anterior cingulate activity during emotion is arousal-dependent. NeuroImage 41(2):648–655

    PubMed  Google Scholar 

  • Menon V (2011) Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cognit Sci 15(10):483–506

    Google Scholar 

  • Muehlhan M, Lueken U, Wittchen HU, Kirschbaum C (2011) The scanner as a stressor: evidence from subjective and neuroendocrine stress parameters in the time course of a functional magnetic resonance imaging session. Int J Psychophysiol 79(2):118–126

    PubMed  Google Scholar 

  • Muehlhan M, Lueken U, Siegert J, Wittchen HU, Smolka MN, Kirschbaum C (2013) Enhanced sympathetic arousal in response to FMRI scanning correlates with task induced activations and deactivations. PLoS One 8(8):e72576

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ota M, Hori H, Sato N, Sasayama D, Hattori K, Teraishi T et al (2013) Hypothalamic-pituitary-adrenal axis hyperactivity and brain differences in healthy women. Neuropsychobiology 68(4):205–211

    CAS  PubMed  Google Scholar 

  • Posner MI, Rothbart MK, Sheese BE, Tang Y (2007) The anterior cingulate gyrus and the mechanism of self-regulation. Cognit Affect Behav Neurosci 7(4):391–395

    Google Scholar 

  • Rao S, Yao Y, Ryan J, Li T, Wang D, Zheng C et al (2016) Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: a comprehensive meta-analysis. Sci Rep 6:32687

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rein T (2016) FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change. BioEssays 38(9):894–902

    CAS  PubMed  Google Scholar 

  • Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhe HG (2013) Neural correlates of dysfunctional emotion regulation in major depressive disorder A systematic review of neuroimaging studies. Neurosci Biobehav Rev 37(10 Pt 2):2529–2553

    PubMed  Google Scholar 

  • Schmaal L, Hibar DP, Samann PG, Hall GB, Baune BT, Jahanshad N et al (2017) Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry 22(6):900–909

    CAS  PubMed  Google Scholar 

  • Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B et al (2005) A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62(3):273–281

    PubMed  Google Scholar 

  • Sturm VE, Sollberger M, Seeley WW, Rankin KP, Ascher EA, Rosen HJ et al (2013) Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity. Soc Cognit Affect Neurosci 8(4):468–474

    Google Scholar 

  • Thompson WH, Thelin EP, Lilja A, Bellander BM, Fransson P (2016) Functional resting-state fMRI connectivity correlates with serum levels of the S100B protein in the acute phase of traumatic brain injury. NeuroImage Clin 12:1004–1012

    PubMed  PubMed Central  Google Scholar 

  • Tozzi L, Carballedo A, Wetterling F, McCarthy H, O’Keane V, Gill M et al (2016) Single-nucleotide polymorphism of the FKBP5 gene and childhood maltreatment as predictors of structural changes in brain areas involved in emotional processing in depression. Neuropsychopharmacology 41(2):487–497

    CAS  PubMed  Google Scholar 

  • Tozzi L, Farrell C, Booij L, Doolin K, Nemoda Z, Szyf M et al (2017) Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk factors with structural and functional brain changes in major depression. Neuropsychopharmacology 43:1138

    PubMed  PubMed Central  Google Scholar 

  • Treadway MT, Grant MM, Ding Z, Hollon SD, Gore JC, Shelton RC (2009) Early adverse events, HPA activity and rostral anterior cingulate volume in MDD. PLoS One 4(3):e4887

    PubMed  PubMed Central  Google Scholar 

  • Tylee DS, Kawaguchi DM, Glatt SJ (2013). On the outside, looking in: a review and evaluation of the comparability of blood and brain “-omes”. Am J Med Genet Part B, Neuropsychiatr Genet 162B(7): 595–603

    CAS  Google Scholar 

  • Vaidya CJ, Gordon EM (2013) Phenotypic variability in resting-state functional connectivity: current status. Brain Connect 3(2):99–120

    PubMed  PubMed Central  Google Scholar 

  • Wager TD, Jonides J, Smith EE, Nichols TE (2005) Toward a taxonomy of attention shifting: individual differences in fMRI during multiple shift types. Cognit Affect Behav Neurosci 5(2):127–143

    Google Scholar 

  • Wang Q, Shelton RC, Dwivedi Y (2018) Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: a systematic review and meta-analysis. J Affect Disord 225:422–428

    CAS  PubMed  Google Scholar 

  • Weber-Goericke, F, Muehlhan, M. (2018): A quantitative meta-analysis of fMRI studies investigating emotional processing in excessive worriers: application of activation likelihood estimation analysis. J Affect Disord (epub ahead of print)

  • White MG, Bogdan R, Fisher PM, Munoz KE, Williamson DE, Hariri AR (2012) FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity. Genes Brain Behav 11(7):869–878

    CAS  PubMed  Google Scholar 

  • Whitfield-Gabrieli S, Nieto-Castanon A (2012) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2(3):125–141

    PubMed  Google Scholar 

  • Whitfield-Gabrieli S, Ghosh SS, Nieto-Castanon A, Saygin Z, Doehrmann O, Chai XJ et al (2016) Brain connectomics predict response to treatment in social anxiety disorder. Mol Psychiatry 21(5):680–685

    CAS  PubMed  Google Scholar 

  • Williams LM, Kemp AH, Felmingham K, Barton M, Olivieri G, Peduto A et al (2006) Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. NeuroImage 29(2):347–357

    PubMed  Google Scholar 

  • Zannas AS, Binder EB (2014) Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes Brain Behav 13(1):25–37

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Psychology, Faculty of Human Sciences, Medical School Hamburg, Am Kaiserkai 1, 20457, Hamburg, Germany

    Markus Muehlhan & Nina Alexander

  2. Neuroimaging Centre, Technische Universität Dresden, Dresden, Germany

    Markus Muehlhan & Michael N. Smolka

  3. Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    Markus Muehlhan & Jens Strehle

  4. Department of Psychology, Institute of General Psychology, Biopsychology and Methods of Psychology, Technische Universität Dresden, Dresden, Germany

    Robert Miller

  5. Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    Michael N. Smolka

Authors
  1. Markus Muehlhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens Strehle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael N. Smolka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Muehlhan.

Ethics declarations

Ethical statement

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.

Conflict of interest

The authors have nothing to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 451 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-019-01980-z

Keywords

Search

Navigation