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



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.


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.


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.


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.


  • 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.


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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).

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Authors and Affiliations



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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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).

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