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Childhood maltreatment and methylation of FK506 binding protein 5 gene (FKBP5)

Published online by Cambridge University Press:  04 November 2015

Audrey R. Tyrka ,
Kathryn K. Ridout ,
Stephanie H. Parade ,
Alison Paquette ,
Carmen J. Marsit  and
Ronald Seifer
Audrey R. Tyrka*
Affiliation:
Butler Hospital Brown University Alpert Medical School
Kathryn K. Ridout
Affiliation:
Butler Hospital Brown University Alpert Medical School
Stephanie H. Parade
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
Alison Paquette
Affiliation:
Dartmouth College Geisel School of Medicine
Carmen J. Marsit
Affiliation:
Dartmouth College Geisel School of Medicine
Ronald Seifer
Affiliation:
Brown University Alpert Medical School E. P. Bradley Hospital
*
Address correspondence and reprint requests to: Audrey Tyrka, 345 Blackstone Boulevard, Providence, RI 02906; E-mail: [email protected].
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Abstract

A growing body of evidence suggests that alterations of the stress response system may be a mechanism by which childhood maltreatment alters risk for psychopathology. FK506 binding protein 51 (FKBP5) binds to the glucocorticoid receptor and alters its ability to respond to stress signaling. The aim of the present study was to examine methylation of the FKBP5 gene (FKBP5), and the role of an FKBP5 genetic variant, in relation to childhood maltreatment in a sample of impoverished preschool-aged children. One hundred seventy-four families participated in this study, including 69 with child welfare documentation of moderate to severe maltreatment in the past 6 months. The children, who ranged in age from 3 to 5 years, were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors; and a composite variable assessed the number exposures to these adversities. Methylation of two sites in intron 7 of FKBP5 was measured via sodium bisulfite pyrosequencing. Maltreated children had significantly lower levels of methylation at both CpG sites (p < .05). Lifetime contextual stress exposure showed a trend for lower levels of methylation at one of the sites, and a trend for an interaction with the FKBP5 polymorphism. A composite adversity variable was associated with lower levels of methylation at one of the sites as well (p < .05). FKBP5 alters glucocorticoid receptor responsiveness, and FKBP5 gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

Type
Regular Articles
Information
Development and Psychopathology , Volume 27 , Special Issue 4pt2: Multilevel Developmental Perspectives on Child Maltreatment , November 2015 , pp. 1637 - 1645
Copyright
Copyright © Cambridge University Press 2015 

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References

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
Bauer, M. E., Jeckel, C. M., & Luz, C. (2009). The role of stress factors during aging of the immune system. Annals of the New York Academy of Sciences, 1153, 139–152.Google Scholar
Beauchaine, T. P., Crowell, S. E., & Hsiao, R. C. (2015). Post-dexamethasone cortisol, self-inflicted injury, and suicidal ideation among depressed adolescent girls. Journal of Abnormal Child Psychology, 43, 619–632.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(Suppl. 1), S186–S195.Google Scholar
Booij, L., Wang, D., Levesque, M. L., Tremblay, R. E., & Szyf, M. (2013). Looking beyond the DNA sequence: The relevance of DNA methylation processes for the stress-diathesis model of depression. Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences. Advance online publication.Google Scholar
Briggs-Gowan, M. J., Carter, A. S., Bosson-Heenan, J., Guyer, A. E., & Horwitz, S. M. (2006). Are infant–toddler social–emotional and behavioral problems transient? Journal of the American Academy of Child & Adolescent Psychiatry, 45, 849–858.Google Scholar
Brown, G. R., & Anderson, B. (1991). Psychiatric morbidity in adult inpatients with childhood histories of sexual and physical abuse. American Journal of Psychiatry, 148, 55–61.Google Scholar
Bryer, J. B., Nelson, B. A., Miller, J. B., & Krol, P. A. (1987). Childhood sexual and physical abuse as factors in adult psychiatric illness. American Journal of Psychiatry, 144, 1426–1430.Google Scholar
Cameron, H. A., & Gould, E. (1994). Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience, 61, 203–209.Google Scholar
Carpenter, L. L., Carvalho, J. P., Tyrka, A. R., Wier, L. M., Mello, A. F., Mello, M. F., et al. (2007). Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biological Psychiatry, 62, 1080–1087.Google Scholar
Carpenter, L. L., Shattuck, T. T., Tyrka, A. R., Geracioti, T. D., & Price, L. H. (2011). Effect of childhood physical abuse on cortisol stress response. Psychopharmacology (Berl), 214, 367–375.CrossRefGoogle ScholarPubMed
Carpenter, L. L., Tyrka, A. R., Ross, N. S., Khoury, L., Anderson, G. M., & Price, L. H. (2009). Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biological Psychiatry, 66, 69–75.Google Scholar
Carr, C. P., Martins, C. M., Stingel, A. M., Lemgruber, V. B., & Juruena, M. F. (2013). The role of early life stress in adult psychiatric disorders: A systematic review according to childhood trauma subtypes. Journal of Nervous and Mental Disease, 201, 1007–1020.Google Scholar
Cicchetti, D. (2015). Neural plasticity, sensitive periods, and psychopathology. Development and Psychopathology, 27, 319–320.Google Scholar
Cicchetti, D., Handley, E. D., & Rogosch, F. A. (2015). Child maltreatment, inflammation, and internalizing symptoms: Investigating the roles of C-reactive protein, gene variation, and neuroendocrine regulation. Development and Psychopathology, 27, 553–566.Google Scholar
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.Google Scholar
Ciufolini, S., Dazzan, P., Kempton, M. J., Pariante, C., & Mondelli, V. (2014). HPA axis response to social stress is attenuated in schizophrenia but normal in depression: Evidence from a meta-analysis of existing studies. Neuroscience & Biobehavioral Reviews, 47, 359–368.Google Scholar
Colich, N. L., Kircanski, K., Foland-Ross, L. C., & Gotlib, I. H. (2015). HPA-axis reactivity interacts with stage of pubertal development to predict the onset of depression. Psychoneuroendocrinology, 55, 94–101.Google Scholar
Dachir, S., Kadar, T., Robinzon, B., & Levy, A. (1993). Cognitive deficits induced in young rats by long-term corticosterone administration. Behavioral and Neural Biology, 60, 103–109.Google Scholar
Daskalakis, N. P., Lehrner, A., & Yehuda, R. (2013). Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinology and Metabolism Clinics, 42, 503–513.CrossRefGoogle ScholarPubMed
de Kloet, C. S., Vermetten, E., Geuze, E., Kavelaars, A., Heijnen, C. J., & Westenberg, H. G. (2006). Assessment of HPA-axis function in posttraumatic stress disorder: Pharmacological and non-pharmacological challenge tests, a review. Journal of Psychiatric Research, 40, 550–567.Google Scholar
de Kloet, C. S., Vermetten, E., Lentjes, E., Geuze, E., van Pelt, J., Manuel, R., et al. (2008). Differences in the response to the combined DEX-CRH test between PTSD patients with and without co-morbid depressive disorder. Psychoneuroendocrinology, 33, 313–320.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.Google Scholar
Doom, J. R., Cicchetti, D., & Rogosch, F. A. (2014). Longitudinal patterns of cortisol regulation differ in maltreated and nonmaltreated children. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 1206–1215.Google Scholar
Dozier, M., Manni, M., Gordon, M. K., Peloso, E., Gunnar, M. R., Stovall-McClough, K. C., et al. (2006). Foster children's diurnal production of cortisol: An exploratory study. Child Maltreatment, 11, 189–197.Google Scholar
Elzinga, B. M., Roelofs, K., Tollenaar, M. S., Bakvis, P., van Pelt, J., & Spinhoven, P. (2008). Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects. Psychoneuroendocrinology, 33, 227–237.Google Scholar
Endler, G., Greinix, H., Winkler, K., Mitterbauer, G., & Mannhalter, C. (1999). Genetic fingerprinting in mouthwashes of patients after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 24, 95–98.Google Scholar
Ewald, E. R., Wand, G. S., Seifuddin, F., Yang, X., Tamashiro, K. L., Potash, J. B., et al. (2014). Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. Psychoneuroendocrinology, 44, 112–122.Google Scholar
Fries, E., Hesse, J., Hellhammer, J., & Hellhammer, D. H. (2005). A new view on hypocortisolism. Psychoneuroendocrinology, 30, 1010–1016.Google Scholar
Fujii, T., Hori, H., Ota, M., Hattori, K., Teraishi, T., Sasayama, D., et al. (2014). Effect of the common functional FKBP5 variant (rs1360780) on the hypothalamic-pituitary-adrenal axis and peripheral blood gene expression. Psychoneuroendocrinology, 42, 89–97.Google Scholar
Gillespie, C. F., Phifer, J., Bradley, B., & Ressler, K. J. (2009). Risk and resilience: Genetic and environmental influences on development of the stress response. Depression and Anxiety, 26, 984–992.Google Scholar
Golier, J. A., Caramanica, K., Makotkine, I., Sher, L., & Yehuda, R. (2014). Cortisol response to cosyntropin administration in military veterans with or without posttraumatic stress disorder. Psychoneuroendocrinology, 40, 151–158.Google Scholar
Gonzalez, A. (2013). The impact of childhood maltreatment on biological systems: Implications for clinical interventions. Paediatrics & Child Health, 18, 415–418.Google Scholar
Gould, E., Woolley, C. S., & McEwen, B. S. (1991). Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death. Journal of Comparative Neurology, 313, 479–485.Google Scholar
Guintivano, J., & Kaminsky, Z. A. (2014). Role of epigenetic factors in the development of mental illness throughout life. Neuroscience Research. Advance online publication.Google Scholar
Gunnar, M. R., & Vazquez, D. M. (2001). Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development. Development and Psychopathology, 13, 515–538.Google Scholar
Hart, H., & Rubia, K. (2012). Neuroimaging of child abuse: A critical review. Frontiers of Human Neuroscience, 6, 52.Google Scholar
Hartman, C. A., Hermanns, V. W., de Jong, P. J., & Ormel, J. (2013). Self- or parent report of (co-occurring) internalizing and externalizing problems, and basal or reactivity measures of HPA-axis functioning: A systematic evaluation of the internalizing-hyperresponsivity versus externalizing-hyporesponsivity HPA-axis hypothesis. Biological Psychology, 94, 175–184.Google Scholar
Heim, C., Ehlert, U., & Hellhammer, D. H. (2000). The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25, 1–35.Google Scholar
Heim, C., Newport, D. J., Bonsall, R., Miller, A. H., & Nemeroff, C. B. (2001). Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. American Journal of Psychiatry, 158, 575–581.Google Scholar
Heim, C., Newport, D. J., Heit, S., Graham, Y. P., Wilcox, M., Bonsall, R., et al. (2000). Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. Journal of the Americans Medical Association, 284, 592–597.Google Scholar
Herman, J. P., McKlveen, J. M., Solomon, M. B., Carvalho-Netto, E., & Myers, B. (2012). Neural regulation of the stress response: Glucocorticoid feedback mechanisms. Brazilian Journal of Medical and Biological Research, 45, 292–298.Google Scholar
Hickman, L. J., Jaycox, L. H., Setodji, C. M., Kofner, A., Schultz, D., Barnes-Proby, D., et al. (2013). How much does “how much” matter? Assessing the relationship between children's lifetime exposure to violence and trauma symptoms, behavior problems, and parenting stress. Journal of Interpersonal Violence, 28, 1338–1362.Google Scholar
Hohne, N., Poidinger, M., Merz, F., Pfister, H., Bruckl, T., Zimmermann, P., et al. (2015). FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls. International Journal of Neuropsychopharmacology. Advance online publication.Google Scholar
Ising, M., Depping, A. M., Siebertz, A., Lucae, S., Unschuld, P. G., Kloiber, S., et al. (2008). Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. European Journal Neuroscience, 28, 389–398.Google Scholar
Januar, V., Saffery, R., & Ryan, J. (2015). Epigenetics and depressive disorders: A review of current progress and future directions. International Journal of Epidemiology. Advance online publication.Google Scholar
Kadmiel, M., & Cidlowski, J. A. (2013). Glucocorticoid receptor signaling in health and disease. Trends in Pharmacological Sciences, 34, 518–530.Google Scholar
Kendler, K. S., Kessler, R. C., Neale, M. C., Heath, A. C., & Eaves, L. J. (1993). The prediction of major depression in women: Toward an integrated etiologic model. American Journal of Psychiatry, 150, 1139–1148.Google Scholar
Kim-Spoon, J., Cicchetti, D., & Rogosch, F. A. (2013). A longitudinal study of emotion regulation, emotion lability-negativity, and internalizing symptomatology in maltreated and nonmaltreated children. Child Development, 84, 512–527.Google Scholar
Klaassens, E. R., van Noorden, M. S., Giltay, E. J., van Pelt, J., van Veen, T., & Zitman, F. G. (2009). Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology. Progress in Neuropsychopharmacology & Biological Psychiatry, 33, 889–894.Google Scholar
Klengel, T., & Binder, E. B. (2015a). Epigenetics of stress-related psychiatric disorders and gene x environment interactions. Neuron, 86, 1343–1357.Google Scholar
Klengel, T., & Binder, E. B. (2015b). FKBP5 allele-specific epigenetic modification in gene by environment interaction. Neuropsychopharmacology, 40, 244–246.Google Scholar
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., et al. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neuroscience, 16, 33–41.Google Scholar
Klengel, T., Pape, J., Binder, E. B., & Mehta, D. (2014). The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology, 80, 115–132.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.Google Scholar
Lee, R. S., Tamashiro, K. L., Yang, X., Purcell, R. H., Huo, Y., Rongione, M., et al. (2011). A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice. Psychopharmacology (Berlin), 218, 303–312.Google Scholar
Leszczynska-Rodziewicz, A., Szczepankiewicz, A., Narozna, B., Skibinska, M., Pawlak, J., Dmitrzak-Weglarz, M., et al. (2014). Possible association between haplotypes of the FKBP5 gene and suicidal bipolar disorder, but not with melancholic depression and psychotic features, in the course of bipolar disorder. Neuropsychiatric Disease and Treatment, 10, 243–248.Google Scholar
Lewinsohn, P. M., Hoberman, H. M., & Rosenbaum, M. (1988). A prospective study of risk factors for unipolar depression. Journal of Abnormal Psychology, 97, 251–264.Google Scholar
Lutz, P. E., Almeida, D., Fiori, L. M., & Turecki, G. (2015). Childhood maltreatment and stress-related psychopathology: The epigenetic memory hypothesis. Current Pharmaceutical Design, 21, 1413–1417.Google Scholar
Lutz, P. E., & Turecki, G. (2014). DNA methylation and childhood maltreatment: From animal models to human studies. Neuroscience, 264, 142–156.Google Scholar
Magarinos, A. M., Orchinik, M., & McEwen, B. S. (1998). Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: A paradox. Brain Research, 809, 314–318.Google Scholar
Magee, J. A., Chang, L. W., Stormo, G. D., & Milbrandt, J. (2006). Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Endocrinology, 147, 590–598.Google Scholar
Marsman, R., Swinkels, S. H., Rosmalen, J. G., Oldehinkel, A. J., Ormel, J., & Buitelaar, J. K. (2008). HPA-axis activity and externalizing behavior problems in early adolescents from the general population: The role of comorbidity and gender the TRAILS study. Psychoneuroendocrinology, 33, 789–798.Google Scholar
McCrory, E., De Brito, S. A., & Viding, E. (2010). Research review: The neurobiology and genetics of maltreatment and adversity. Journal of Child Psychology and Psychiatry, 51, 1079–1095.Google Scholar
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87, 873–904.Google Scholar
Menke, A., Klengel, T., Rubel, J., Bruckl, T., Pfister, H., Lucae, S., et al. (2013). Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression. Genes, Brain, and Behavior, 12, 289–296.Google Scholar
Mesman, J., & Koot, H. M. (2001). Early preschool predictors of preadolescent internalizing and externalizing DSM-IV diagnoses. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 1029–1036.Google Scholar
Mills, R., Scott, J., Alati, R., O'Callaghan, M., Najman, J. M., & Strathearn, L. (2013). Child maltreatment and adolescent mental health problems in a large birth cohort. Child Abuse & Neglect, 37, 292–302.Google Scholar
Morris, M. C., Compas, B. E., & Garber, J. (2012). Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: A systematic review and meta-analysis. Clinical Psychology Review, 32, 301–315.Google Scholar
Nanni, V., Uher, R., & Danese, A. (2012). Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: A meta-analysis. American Journal of Psychiatry, 169, 141–151.Google Scholar
Norman, R. E., Byambaa, M., De, R., Butchart, A., Scott, J., & Vos, T. (2012). The long-term health consequences of child physical abuse, emotional abuse, and neglect: A systematic review and meta-analysis. PLOS Medicine, 9, e1001349.Google Scholar
Nugent, N. R., Tyrka, A. R., Carpenter, L. L., & Price, L. H. (2011). Gene-environment interactions: Early life stress and risk for depressive and anxiety disorders. Psychopharmacology (Berlin), 214, 175–196.Google 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.Google Scholar
Philip, N. S., Sweet, L. H., Tyrka, A. R., Carpenter, S. L., Albright, S. E., Price, L. H., et al. (2015). Exposure to childhood trauma is associated with altered n-back activation and performance in healthy adults: Implications for a commonly used working memory task. Brain Imaging and Behavior. Advance online publication.Google Scholar
Pryce, C. R., Ruedi-Bettschen, D., Dettling, A. C., Weston, A., Russig, H., Ferger, B., et al. (2005). Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research. Neuroscience & Biobehavioral Reviews, 29, 649–674.Google Scholar
Radtke, K. M., Schauer, M., Gunter, H. M., Ruf-Leuschner, M., Sill, J., Meyer, A., et al. (2015). Epigenetic modifications of the glucocorticoid receptor gene are associated with the vulnerability to psychopathology in childhood maltreatment. Translational Psychiatry, 5, e571.Google Scholar
Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425–432.Google Scholar
Ridout, K. K., Parade, S. H., Seifer, R., Price, L. H., Gelernter, J., Feliz, P., et al. (2014). Interleukin 1B gene (IL1B) variation and internalizing symptoms in maltreated preschoolers. Development and Psychopathology, 26(4, Part 2), 1277–1287.Google Scholar
Ridout, S. J., Ridout, K. K., Kao, H. T., Carpenter, L. L., Philip, N. S., Tyrka, A. R., et al. (2015). Telomeres, early-life stress and mental illness. Advances in Psychosomatic Medicine, 34, 92–108.Google Scholar
Rohleder, N., Joksimovic, L., Wolf, J. M., & Kirschbaum, C. (2004). Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biological Psychiatry, 55, 745–751.Google Scholar
Roza, S. J., Hofstra, M. B., van der Ende, J., & Verhulst, F. C. (2003). Stable prediction of mood and anxiety disorders based on behavioral and emotional problems in childhood: A 14-year follow-up during childhood, adolescence, and young adulthood. American Journal of Psychiatry, 160, 2116–2121.Google Scholar
Sarapas, C., Cai, G., Bierer, L. M., Golier, J. A., Galea, S., Ising, M., et al. (2011). Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks. Disease Markers, 30, 101–110.Google Scholar
Sasaki, A., de Vega, W. C., & McGowan, P. O. (2013). Biological embedding in mental health: An epigenomic perspective. Biochemistry and Cell Biology, 91, 14–21.Google Scholar
Scheeringa, M. S., & Haslett, N. (2010). The reliability and criterion validity of the Diagnostic Infant and Preschool Assessment: A new diagnostic instrument for young children. Child Psychiatry and Human Development, 41, 299–312.Google Scholar
Schmidt, U., Buell, D. R., Ionescu, I. A., Gassen, N. C., Holsboer, F., Cox, M. B., et al. (2015). A role for synapse in in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. Psychoneuroendocrinology, 52, 43–58.Google Scholar
Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., et al. (2015). DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain. American Journal of Medical Genetics, 168B, 36–44.Google Scholar
Spijker, A. T., & van Rossum, E. F. (2012). Glucocorticoid sensitivity in mood disorders. Neuroendocrinology, 95, 179–186.Google Scholar
Stankiewicz, A. M., Swiergiel, A. H., & Lisowski, P. (2013). Epigenetics of stress adaptations in the brain. Brain Research Bulletin, 98, 76–92.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.Google Scholar
Suzuki, H., Belden, A. C., Spitznagel, E., Dietrich, R., & Luby, J. L. (2013). Blunted stress cortisol reactivity and failure to acclimate to familiar stress in depressed and sub-syndromal children. Psychiatry Research, 210, 575–583.Google Scholar
Szczepankiewicz, A., Leszczynska-Rodziewicz, A., Pawlak, J., Narozna, B., Rajewska-Rager, A., Wilkosc, M., et al. (2014). FKBP5 polymorphism is associated with major depression but not with bipolar disorder. Journal of Affective Disorders, 164, 33–37.Google Scholar
Szyf, M. (2011). The early life social environment and DNA methylation: DNA methylation mediating the long-term impact of social environments early in life. Epigenetics, 6, 971–978.Google Scholar
Szyf, M. (2015). Nongenetic inheritance and transgenerational epigenetics. Trends in Molecular Medicine, 21, 134–144.Google Scholar
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.Google Scholar
Thiede, C., Prange-Krex, G., Freiberg-Richter, J., Bornhauser, M., & Ehninger, G. (2000). Buccal swabs but not mouthwash samples can be used to obtain pretransplant DNA fingerprints from recipients of allogeneic bone marrow transplants. Bone Marrow Transplantation, 25, 575–577.Google Scholar
Toth, S. L., Gravener-Davis, J. A., Guild, D. J., & Cicchetti, D. (2013). Relational interventions for child maltreatment: Past, present, and future perspectives. Development Psychopathology, 25(4, Part 2), 1601–1617.Google Scholar
Turecki, G., & Meaney, M. J. (2014). Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry. Advance online publication.Google Scholar
Tyrka, A. R., Burgers, D. E., Philip, N. S., Price, L. H., & Carpenter, L. L. (2013). The neurobiological correlates of childhood adversity and implications for treatment. Acta Psychiatrica Scandinavica, 128, 434–447.Google Scholar
Tyrka, A. R., Parade, S. H., Eslinger, N. M., Marsit, C. J., Lesseur, C., Armstrong, D. A., et al. (2015). Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children. Development and Psychopathology, 27, 577–585.Google Scholar
Tyrka, A. R., Parade, S. H., Price, L. H., Kao, H. T., Porton, B., Philip, N. S., et al. (2015). Alterations of mitochondrial DNA copy number and telomere length with early adversity and psychopathology. Biological Psychiatry. Advance online publication.Google Scholar
Tyrka, A. R., Price, L. H., Gelernter, J., Schepker, C., Anderson, G. M., & Carpenter, L. L. (2009). Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: Effects on hypothalamic-pituitary-adrenal axis reactivity. Biological Psychiatry, 66, 681–685.Google Scholar
Tyrka, A. R., Price, L. H., Kao, H. T., Porton, B., Marsella, S. A., & Carpenter, L. L. (2010). Childhood maltreatment and telomere shortening: Preliminary support for an effect of early stress on cellular aging. Biological Psychiatry, 67, 531–534.Google Scholar
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLOS ONE, 7, e30148.Google Scholar
Tyrka, A. R., Wier, L., Price, L. H., Ross, N., Anderson, G. M., Wilkinson, C. W., et al. (2008). Childhood parental loss and adult hypothalamic-pituitary-adrenal function. Biological Psychiatry, 63, 1147–1154.Google Scholar
van der Knaap, L. J., Oldehinkel, A. J., Verhulst, F. C., van Oort, F. V., & Riese, H. (2015). Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents: The TRAILS study. Psychoneuroendocrinology, 58, 46–50.Google Scholar
van der Knaap, L. J., van Oort, F. V., Verhulst, F. C., Oldehinkel, A. J., & Riese, H. (2015). Methylation of NR3C1 and SLC6A4 and internalizing problems: The TRAILS study. Journal of Affective Disorders, 180, 97–103.Google Scholar
Vandevyver, S., Dejager, L., & Libert, C. (2014). Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocrine Reviews, 35, 671–693.Google Scholar
Van Zomeren-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.Google Scholar
Wagner, J. R., Busche, S., Ge, B., Kwan, T., Pastinen, T., & Blanchette, M. (2014). The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biology, 15, R37.Google Scholar
Watanabe, Y., Gould, E., & McEwen, B. S. (1992). Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Research, 588, 341–345.Google Scholar
Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., et al. (2014). Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 417–424.Google Scholar
Widom, C. S., DuMont, K., & Czaja, S. J. (2007). A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Archives of General Psychiatry, 64, 49–56.Google Scholar
Wolkowitz, O. M., Epel, E. S., Reus, V. I., & Mellon, S. H. (2010). Depression gets old fast: Do stress and depression accelerate cell aging? Depression and Anxiety, 27, 327–338.Google Scholar
Woolley, C. S., Gould, E., & McEwen, B. S. (1990). Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Research, 531, 225–231.Google Scholar
Yang, X., Han, H., De Carvalho, D. D., Lay, F. D., Jones, P. A., & Liang, G. (2014). Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell, 26, 577–590.Google Scholar
Yehuda, R., Cai, G., Golier, J. A., Sarapas, C., Galea, S., Ising, M., et al. (2009). Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biological Psychiatry, 66, 708–711.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.Google Scholar
Zhang, T. Y., Labonte, B., Wen, X. L., Turecki, G., & Meaney, M. J. (2013). Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology, 38, 111–123.Google Scholar