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Epigenetic differences in stress response gene FKBP5 among children with abusive vs accidental injuries

Pediatric Research (2023)Cite this article

Abstract

Background

Survivors of child abuse experience high rates of adverse physical and mental health outcomes. Epigenetic alterations in the stress response system, the FKBP5 gene specifically, have been implicated as one mechanism that may link abuse to lifelong health issues. Prior studies primarily included older individuals with a remote history of maltreatment; our objective was to test for differential methylation of FKBP5 in children with abusive vs accidental injuries at the time of diagnosis.

Methods

We conducted a cross-sectional pilot study of acutely injured children <4 years old at two children’s hospitals (n = 82). Research personnel collected injury histories, buccal swabs (n = 65), and blood samples (n = 25) to measure DNA methylation. An expert panel classified the injuries as abusive, accidental, or indeterminate.

Results

Children with abusive as compared to accidental injuries had lower methylation of the FKBP5 promoter in buccal and blood cells, even after controlling for injury severity, socioeconomic status, and psychosocial risk factors.

Conclusion

These findings suggest that epigenetic variation in FKBP5 may occur at the earliest indication of abuse and may be associated with delayed resolution of the HPA axis stress response. Additional testing for epigenetic differences in larger sample sizes is needed to further verify these findings.

Impact

  • Children (<4 years old) with abusive compared to accidental injuries showed lower methylation of the FKBP5 promoter in buccal and blood cells at the time of initial diagnosis even after controlling for injury severity, socioeconomic status, and psychosocial risk factors.

  • Early childhood physical abuse may impact the epigenetic regulation of the stress response system, including demethylation within promoters and enhancers of the FKBP5 gene, even at the earliest indication of abuse.

  • The findings are important because unmitigated stress is associated with adverse health outcomes throughout the life-course.

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Fig. 1: Manhattan-style plot demonstrating the statistical significance (y-axis) and genomic locations (x-axis) of abuse-associated differential DNA methylation at CpGs within the FKBP5 locus (from both buccal and blood cells).

Data availability

The datasets generated and analyzed during the current study may be available from the corresponding author upon reasonable request.

References

  1. Christian, C. W., Committee on Child Abuse and Neglect, American Academy of Pediatrics. The evaluation of suspected child physical abuse. Pediatrics 135, e1337–e1354 (2015).

    Article  Google Scholar 

  2. Shonkoff, J. P. & Garner, A. S. Committee on Psychosocial Aspects of Child and Family Health; Committee on Early Childhood, Adoption, and Dependent Care; Section on Developmental and Behavioral Pediatrics. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129, e232–e246 (2012).

    Article  Google Scholar 

  3. Nothling, J., Malan-Muller, S., Abrahams, N., Hemmings, S. M. J. & Seedat, S. Epigenetic alterations associated with childhood trauma and adult mental health outcomes: a systematic review. World J. Biol. Psychiatry 21, 493–512 (2020).

    Article  Google Scholar 

  4. Jiang, S., Postovit, L., Cattaneo, A., Binder, E. B. & Aitchison, K. J. Epigenetic modifications in stress response genes associated with childhood trauma. Front. Psychiatry 10, 808 (2019).

    Article  Google Scholar 

  5. Alexander, N., Kirschbaum, C., Stalder, T., Muehlhan, M. & Vogel, S. No association between FKBP5 gene methylation and acute and long-term cortisol output. Transl. Psychiatry 10, 175 (2020).

    Article  CAS  Google Scholar 

  6. Harms, M. B. et al. Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: a prospective longitudinal study. Dev. Psychopathol. 29, 1895–1903 (2017).

    Article  Google Scholar 

  7. Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosc. 16, 33–41 (2013).

    Article  CAS  Google Scholar 

  8. Misiak, B. et al. Adverse childhood experiences and methylation of the FKBP5 gene in patients with psychotic disorders. J. Clin. Med. 9, 3792 (2020).

    Article  CAS  Google Scholar 

  9. Tozzi, L. et al. Epigenetic changes of FKBP5 as a link connecting genetic and environmental risk factors with structural and functional brain changes in major depression. Neuropsychopharmacology 43, 1138–1145 (2018).

    Article  CAS  Google Scholar 

  10. Bustamante, A. C. et al. FKBP5 DNA methylation does not mediate the association between childhood maltreatment and depression symptom severity in the Detroit Neighborhood Health Study. J. Psychiatr. Res. 96, 39–48 (2018).

    Article  Google Scholar 

  11. Farrell, C. et al. DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse. Psychiatry Res. 265, 341–348 (2018).

    Article  CAS  Google Scholar 

  12. Klinger-Konig, J. et al. Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression. Neuropsychopharmacology 44, 930–938 (2019).

    Article  Google Scholar 

  13. Yeo, S. et al. The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure. Genes Brain Behav. 16, 223–232 (2017).

    Article  CAS  Google Scholar 

  14. Fortin, J. P. et al. Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol. 15, 503 (2014).

    Article  Google Scholar 

  15. Pidsley, R. et al. Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling. Genome Biol. 17, 208 (2016).

    Article  Google Scholar 

  16. Zheng, S. C. et al. A novel cell-type deconvolution algorithm reveals substantial contamination by immune cells in saliva, buccal and cervix. Epigenomics 10, 925–940 (2018).

    Article  CAS  Google Scholar 

  17. Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012).

    Article  CAS  Google Scholar 

  18. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article  CAS  Google Scholar 

  19. Fishilevich, S., et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford) 2017, bax028 (2017).

  20. Braun, P. R. et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl. Psychiatry 9, 47 (2019).

    Article  Google Scholar 

  21. Parade, S. H. et al. Change in FK506 binding protein 5 (FKBP5) methylation over time among preschoolers with adversity. Dev. Psychopathol. 29, 1627–1634 (2017).

    Article  Google Scholar 

  22. Weder, N. et al. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J. Am. Acad. Child Adolesc. Psychiatry 53, 417–424.e5 (2014).

    Article  Google Scholar 

  23. Paakinaho, V., Makkonen, H., Jaaskelainen, T. & Palvimo, J. J. Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol. Endocrinol. 24, 511–525 (2010).

    Article  CAS  Google Scholar 

  24. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).

    Article  CAS  Google Scholar 

  25. Zannas, A. S. et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk. Proc. Natl Acad. Sci. Usa. 116, 11370–11379 (2019).

    Article  CAS  Google Scholar 

  26. Estupiñán-Moreno, E. et al. Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids. Ann. Rheum. Dis. 81, 1290–1300 (2022).

    Article  Google Scholar 

  27. Wochnik, G. M. et al. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J. Biol. Chem. 280, 4609–4616 (2005).

    Article  CAS  Google Scholar 

  28. Braun, P. R. et al. Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples. Psychiatry Clin. Neurosci. 73, 323–330 (2019).

    Article  CAS  Google Scholar 

  29. Glad, C. et al. Reduced DNA methylation and psychopathology following endogenous hypercortisolism – a genome-wide study. Sci. Rep. 7, 44445 (2017).

    Article  CAS  Google Scholar 

  30. Zannas, A. S., Wiechmann, T., Gassen, N. C. & Binder, E. B. Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacol 41, 261–274 (2016).

    Article  CAS  Google Scholar 

  31. Matosin, N., et al. Brain expressed FKBP5 delineates a therapeutic subtype of severe mental illness. Preprint at bioRxiv (2021).

  32. Smith, A. K. et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 168B, 36–44 (2015).

    Article  Google Scholar 

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Funding

This study was funded by the Stanley Manne Research Center, Visionary Award, Ann & Robert H. Lurie Children’s Hospital of Chicago. This study was also funded, in part, by the Grainger Research Initiative Fund in Emergency Medicine at Lurie Children’s Hospital. T.M.E. receives support from the HERCULES Center (NIEHS P30ES019776).

Author information

Authors and Affiliations

  1. Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA

    Todd M. Everson

  2. Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA

    Todd M. Everson

  3. Mary Ann and J. Milburn Smith Child Health Outreach, Research, and Evaluation Center, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Kim Kaczor

  4. Mayerson Center for Safe and Healthy Children, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Kathi Makoroff

  5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Kathi Makoroff

  6. Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Gabriel Meyers

  7. Division of Child Abuse Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Norell Rosado, Elizabeth Charleston, Audrey Young & Mary Clyde Pierce

  8. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Norell Rosado & Mary Clyde Pierce

  9. Department of Bioengineering, J.B. Speed School of Engineering, University of Louisville, Louisville, KY, USA

    Gina Bertocci

  10. McGaw Medical Center of Northwestern University, Chicago, IL, USA

    Audrey Young

  11. Division of Emergency Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Janet Flores, Katie Lehnig & Mary Clyde Pierce

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  1. Todd M. Everson
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Contributions

T.M.E. carried out the analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. K.K. conceptualized and designed the study including data collection instruments, collected data and/or supervised data collection, participated in data analysis, drafted the initial manuscript, and critically reviewed the manuscript. K.M. conceptualized and designed the study including data collection instruments, collected data and/or supervised data collection, and critically reviewed the manuscript. G.M., E.C., J.F., and K.L. collected data and/or supervised data collection and critically reviewed the manuscript. G.B. and N.R. provided expert opinion on data and critically reviewed the manuscript. A.Y. participated in data analysis and critically reviewed and revised the manuscript. M.C.P. conceptualized and designed the study including data collection instruments, collected data and/or supervised data collection, participated in data analysis, provided expert opinion on data, drafted the initial manuscript, and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Mary Clyde Pierce.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

For patients undergoing abuse evaluations, a waiver of authorization was granted to avoid interference with the evaluation process. For patients not undergoing an abuse evaluation, informed consent was obtained from legal guardians. This study was reviewed and approved by both Lurie Children’s Hospital and Cincinnati Children’s Hospital Institutional Review Boards (IRBs).

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Everson, T.M., Kaczor, K., Makoroff, K. et al. Epigenetic differences in stress response gene FKBP5 among children with abusive vs accidental injuries. Pediatr Res (2023). https://doi.org/10.1038/s41390-022-02441-w

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  • DOI: https://doi.org/10.1038/s41390-022-02441-w

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