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Methylation matters: FK506 binding protein 51 (FKBP5) methylation moderates the associations of FKBP5 genotype and resistant attachment with stress regulation

  • Rosa H. Mulder (a1) (a2), Jolien Rijlaarsdam (a1) (a2), Maartje P. C. M. Luijk (a2) (a3), Frank C. Verhulst (a2), Janine F. Felix (a2), Henning Tiemeier (a2), Marian J. Bakermans-Kranenburg (a1) and Marinus H. Van Ijzendoorn (a1) (a2)...


The parent–child attachment relationship plays an important role in the development of the infant's stress regulation system. However, genetic and epigenetic factors such as FK506 binding protein 51 (FKBP5) genotype and DNA methylation have also been associated with hypothalamus–pituitary–adrenal axis functioning. In the current study, we examined how parent–child dyadic regulation works in concert with genetic and epigenetic aspects of stress regulation. We study the associations of attachment, extreme maternal insensitivity, FKBP5 single nucleotide polymorphism 1360780, and FKBP5 methylation, with cortisol reactivity to the Strange Situation Procedure in 298 14-month-old infants. The results indicate that FKBP5 methylation moderates the associations of FKBP5 genotype and resistant attachment with cortisol reactivity. We conclude that the inclusion of epigenetics in the field of developmental psychopathology may lead to a more precise picture of the interplay between genetic makeup and parenting in shaping stress reactivity.


Corresponding author

Address correspondence and reprint requests to: Marinus van IJzendoorn or Marian Bakermans-Kranenburg, Center for Child and Family Studies, Leiden University, PO Box 9555, 2300 RB Leiden, the Netherlands; E-mail: or


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The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam School of Law and Faculty of Social Sciences, the Municipal Health Service Rotterdam, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The Generation R Study is made possible by financial support from Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; and the Netherlands Organization for Health Research and Development (ZonMw). The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by a grant from the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research Netherlands Consortium for Healthy Aging (Project 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, by a grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361), and a Consolidator Grant from the European Research Council (ERC-2014-CoG-64916). We thank Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Higgins, Mr. Marijn Verkerk, and Dr. Lisette Stolk for their help in creating the EWAS database. Janine Felix has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 633595 (DynaHEALTH). Marinus van IJzendoorn and Marian Bakermans-Kranenburg were supported by the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (Gravitation program, SPINOZA, VICI).



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