Hostname: page-component-5f745c7db-f9j5r Total loading time: 0 Render date: 2025-01-06T16:52:13.565Z Has data issue: true hasContentIssue false
  • English
  • Français

Change in FK506 binding protein 5 (FKBP5) methylation over time among preschoolers with adversity

Published online by Cambridge University Press:  22 November 2017

Stephanie H. Parade ,
Justin Parent ,
Kantoniony Rabemananjara ,
Ronald Seifer ,
Carmen J. Marsit ,
Bao-Zhu Yang ,
Huiping Zhang  and
Audrey R. Tyrka
Stephanie H. Parade*
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
Justin Parent
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital Florida International University
Kantoniony Rabemananjara
Affiliation:
E. P. Bradley Hospital
Ronald Seifer
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
Carmen J. Marsit
Affiliation:
Emory University
Bao-Zhu Yang
Affiliation:
Yale University School of Medicine
Huiping Zhang
Affiliation:
Boston University School of Medicine
Audrey R. Tyrka
Affiliation:
Brown University Alpert Medical School Butler Hospital
*
Address correspondence and reprint requests to: Stephanie H. Parade, Bradley Research Center, E. P. Bradley Hospital, 1011 Veterans Memorial Parkway, East Providence, RI 02915; E-mail: [email protected].
Get access Rights & Permissions [Opens in a new window]

Abstract

FK506 binding protein 5 (FKBP5) alters stress response system functioning, and childhood maltreatment is associated with methylation of the FKBP5 gene. Yet it is unknown if maltreatment contributes to change in FKBP5 methylation over time. The current study draws upon a sample of 231 preschoolers, including 123 with child welfare documentation of moderate to severe maltreatment in the past 6 months, to understand if maltreatment contributes to change in FKBP5 methylation over a 6-month period. Review of child protection records and semistructured interviews in the home were used to assess maltreatment and exposure to other contextual stressors, as well as service utilization. Methylation of FKBP5 at two CpG sites in intron 7 was measured from saliva DNA at the time of initial study enrollment, and 6 months following enrollment. Child maltreatment was associated with change in FKBP5 methylation over time, but only when children were exposed to high levels of other contextual stressors. Service utilization was associated with increases in methylation over time, but only among children with the FKPB5 rs1360780 protective CC genotype. Methylation of FKBP5 is sensitive to stress exposure and may be a mechanism linking early adversity to long-term health and developmental outcomes.

Type
Special Issue Articles
Information
Development and Psychopathology , Volume 29 , Special Issue 5: Biological and Behavioral Effects of Early Adversity on Multiple Levels of Development , December 2017 , pp. 1627 - 1634
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

This research was supported by Grant R01 MH083704 awarded to the last author from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIMH. We are grateful to the children and families who participated in this study, and we thank Hasbro Children's Hospital, Rhode Island Head Start, and the Rhode Island Department of Children, Youth, and Families for assisting in recruitment of study participants. We also thank Brittney Josefson and the numerous other research assistants who contributed to this project, and Asi Polly Gobin for data management. Isolation of DNA and the genotyping array were done in the laboratory of Joel Gelernter, MD, and we are grateful to Dr. Gelernter and his staff for their contribution.

References

Aiken, L. S., & West, S. G. (1991). Testing and interpreting interactions in multiple regression. Thousand Oaks, CA: Sage.Google Scholar
Alisch, R. S., Barwick, B. G., Chopra, P., Myrick, L. K., Satten, G. A., Conneely, K. N., & Warren, S. T. (2012). Age-associated DNA methylation in pediatric populations. Genome Research, 22, 623–632. doi:10.1101/gr.125187.11 CrossRefGoogle ScholarPubMed
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 7–73). Norwood, NJ: Ablex.Google Scholar
Binder, E. B. (2009). The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 34, S186–S195. doi:10.1016/j.psyneuen.2009.05.021 Google Scholar
Burns, B. J., Phillips, S. D., Wagner, H. R., Barth, R. P., Kolko, D. J., Campbell, Y., & Landsverk, J. (2004). Mental health need and access to mental health services by youths involved with child welfare: A national survey. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 960–970. doi:10.1097/01.chi.0000127590.95585.65 CrossRefGoogle ScholarPubMed
Cioffi, D. L., Hubler, T. R., & Scammell, J. G. (2011). Organization and function of the FKBP52 and FKBP51 genes. Current Opinion in Pharmacology, 11, 308–313. doi:10.1016/j.coph.2011.03.013 Google Scholar
Cohen, S., Janicki-Deverts, D., & Miller, G. E. (2007). Psychological stress and disease. Journal of the American Medical Association, 298, 1685–1687. doi:10.1001/jama.298.14.1685 Google Scholar
de Kloet, E. R., Joels, M., & Holsboer, F. (2005). Stress and the brain: From adaptation to disease. Nature Reviews Neuroscience, 6, 463–475. doi:10.1038/nrn1683 Google Scholar
Evans, G. W. (2003). A multimethodological analysis of cumulative risk and allostatic load among rural children. Developmental Psychology, 39, 924–933. doi:10.1037/0012-1649.39.5.924 Google Scholar
Gilbert, R., Wisdom, C. S., Browne, K., Fergusson, D., Webb, E., & Janson, S. (2009). Burden and consequences of child maltreatment in high-income countries. Lancet, 373, 68–81. doi:10.1016/S0140-6736(08)61706-7 Google Scholar
Grippo, A. J., & Johnson, A. K. (2009). Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress, 12, 1–21. doi:10.1080/10253890802046281 CrossRefGoogle ScholarPubMed
Han, K., Won, E., Sim, Y., Kang, J., Han, C., Kim, Y., … Ham, B. (2017). Influence of FKBP5 polymorphism and DNA methylation on structural changes of the brain in major depressive disorder. Scientific Reports, 7, 42621. doi:10.1038/srep42621 Google Scholar
Hohne, N., Poidinger, M., Merz, F., Pfister, H., Bruckl, T., Zimmermann, P., … Ising, M. (2015). FKBP5 genotype-dependent DNA methylation and mRNA regulation afterpsychosocial stress in remitted depression and healthy controls. International Journal of Neuropsychopharmacology, 18, pyu087. doi:10.1093/ijnp/pyu087 Google Scholar
Hu, L., & Bentler, P. M. (1999). Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives. Structural Equation Modeling, 6, 1–55. doi:10.1080/10705519909540118 Google Scholar
Ising, M., Depping, A. M., Siebertz, A., Lucae, S., Unschuld, P. G., Kloiber, S., … Holsboer, F. (2008). Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. European Journal Neuroscience, 28, 389–398. doi:10.1111/j.1460-9568.2008.06332.x Google Scholar
Kadmiel, M., & Cidlowski, J. A. (2013). Glucocorticoid receptor signaling in health and disease. Trends in Pharmacological Sciences, 34, 518–530. doi:10.1016/j.tips.2013.07.003 Google Scholar
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., … Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience, 16, 33–41. doi:10.1038/nn.3275 Google Scholar
Laryea, G., Muglia, L., Arnett, M., & Muglia, L. J. (2015). Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic–pituitary–adrenal axis by gene targeting in mice. Frontiers in Neuroendocrinology, 36, 150–164. doi:10.1016/j.yfrne.2014.09.002 CrossRefGoogle ScholarPubMed
Leszczynska-Rodziewicz, A., Szczepankiewicz, A., Narozna, B., Skibinska, M., Pawlak, J., Dmitrzak-Weglarz, M., & Hauser, J. (2014). Possible association between haplotypes of the FKBP5 gene and suicidal disorder, but not with melancholic depression and psychotic features, in the course of bipolar disorder. Neuropsychiatric Disease and Treatment, 10, 243–248. doi:10.2147/NDT.S54538 Google Scholar
Little, R. J. (1988). A test of missing completely at random for multivariate data with missing values. Journal of the American Statistical Association, 83, 1198–1202. doi:10.2307/2290157 Google Scholar
Martino, D., Loke, Y. J., Gordon, L., Ollikainen, M., Cruickshank, M. N., Saffery, R., & Craig, J. M. (2013). Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biology, 14, R42. doi:10.1186/gb-2013-14-5-r42 CrossRefGoogle ScholarPubMed
McArdle, J. J. (2009). Latent variable modeling of differences and changes with longitudinal data. Annual Review of Psychology, 60, 577–605. doi:10.1146/annurev.psych.60.110707.163612 Google Scholar
McEwen, B. S. (2008). Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. European Journal of Pharmacology, 583, 174–185. doi:10.1016/j.ejphar.2007.11.071 CrossRefGoogle ScholarPubMed
Menke, A., Klengel, T., Rubel, J., Brückl, T., Pfister, H., Lucae, S., … Binder, E. B. (2013). Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression. Genes, Brain and Behavior, 12, 289–296. doi:10.1111/gbb.12026 Google Scholar
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 23–38. doi:10.1038/npp.2012.112 Google Scholar
Muthén, L. K., & Muthén, B. O. (1998–2012). Mplus user's guide (6th ed.). Los Angeles: Authors.Google Scholar
Non, A. L., Hollister, B. M., Humphreys, K. L., Childebayeva, A., Esteves, K., Zeanah., C., … Drury, S. (2016). DNA methylation at stress-related genes is associated with exposure to early life institutionalization. American Journal of Physical Anthropology, 61, 84–93. doi:10.1002/ajpa.23010 CrossRefGoogle Scholar
Paquette, A. G., Lester, B. M., Koestler, D. C., Lesseur, C., Armstrong, D. A., & Marsit, C. J. (2014). Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort. PLOS ONE, 9, e104913. doi:10.1371/journal.pone.0104913 CrossRefGoogle ScholarPubMed
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 38, 904–909. doi:10.1038/ng1847 Google Scholar
Purcell, S., Neale, B., Todd-Brown, K., Ferreira, M. A., Bender, D., Maller, J., … Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559–575. doi:10.1086/519795 Google Scholar
Roberts, S., Keers, R., Lester, K. J., Coleman, J. R., Breen, G., Arendt, K., … Wong, C. C. (2015). HPA axis related genes and response to psychological therapies: Genetics and epigenetics. Depression and Anxiety, 32, 861–870. doi:10.1002/da.22430 CrossRefGoogle ScholarPubMed
Schmidt, U., Buell, D. R., Ionescu, I. A., Gassen, N. C., Holsboer, F., Cox, M. B., … Touma, C. (2015). A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. Psychoneuroendocrinology, 52, 43–58. doi:10.1016/j.psyneuen.2014.11.005 CrossRefGoogle ScholarPubMed
Schneiderman, N., Ironson, G., & Siegel, S. D. (2005). Stress and health: Psychological, behavioral, and biological determinants. Annual Review Clinical Psychology, 1, 607–628. doi:10.1146/annurev.clinpsy.1.102803.144141 Google Scholar
Shonkoff, J. P., Boyce, W. T., & McEwen, B. S. (2009). Neuroscience, molecular biology, and the childhood roots of health disparities: Building a new framework for health promotion and disease prevention. Journal of the American Medical Association, 21, 2252–2259. doi:10.1001/jama.2009.754 Google Scholar
Suzuki, A., Matsumoto, Y., Sadahiro, R., Enokido, M., Goto, K., & Otani, K. (2014). Relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression. Comprehensive Psychiatry, 55, 1422–1425. doi:10.1016/j.comppsych.2014.04.019 Google Scholar
Szczepankiewicz, A., Leszczynska-Rodziewicz, A., Pawlak, J., Narozna, B., Rajewska-Rager, A., Wilkosc, M., … Twarowska-Hauser, J. (2014). FKBP5 polymorphism is associated with major depression but not with bipolar disorder. Journal of Affective Disorders, 164, 33–37. doi:10.1016/j.jad.2014.04.002 Google Scholar
Szyf, M. (2007). The dynamic epigenome and its implications in toxicology. Toxicological Sciences, 100, 7–23. doi:10.1093/toxsci/kfm177 CrossRefGoogle ScholarPubMed
Tatro, E. T., Everall, I. P., Kaul, M., & Achim, C. L. (2009). Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: Implications for major depressive disorder. Brain Research, 1286, 1–12. doi:10.1016/j.brainres.2009.06.036 CrossRefGoogle ScholarPubMed
Tyrka, A. R., Parade, S. H., Eslinger, N. M., Seifer, R., Marsit, C. J., Lesseur, C., … Josefson, B. (2015). Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in pre-school aged children. Development and Psychopathology, 27, 577–585. doi:10.1017/S0954579415000176 Google Scholar
US Department of Health and Human Services, Administration for Children and Families, Administration on Children, Youth and Families, Children's Bureau. (2017). Child Maltreatment 2015. Retrieved from http://www.acf.hhs.gov/programs/cb/research-data-technology/statistics-research/child-maltreatment Google Scholar
VanZomeren-Dohm, A. A., Pitula, C. E., Koss, K. J., Thomas, K., & Gunnar, M. R. (2015). FKBP5 moderation of depressive symptoms in peer victimized, post-institutionalized children. Psychoneuroendocrinology, 51, 426–430. doi:10.1016/j.psyneuen.2014.10.003 Google Scholar
Zannas, A. S., & Binder, E. B. (2014). Gene-environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism. Genes, Brain and Behavior, 13, 25–37. doi:10.1111/gbb.12104 Google Scholar