Introduction: Non-suicidal self-injury (NSSI) is a large phenomenon among adolescents, and adverse childhood experiences (ACEs) are a major risk factor in its development. Malfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis has been repeatedly reported for ACE as well as for NSSI. The glucocorticoid receptor (GR) is essential for the correct functioning of the HPA axis, thus alterations in the expression of the GR through altered methylation of the GR gene (NR3C1) (and more specifically exon 1F) might contribute to the development of NSSI in individuals with a history of ACEs, as has been reported for different other mental disorders. Methods: In this case-control study, we compared the methylation levels of exon 1F of the GR gene (NR3C1-1F) in adolescents with engagement in NSSI (n = 67) and a healthy control group (HC; n = 47). We preserved buccal swabs and used a mass spectrometry-based method called EpiTYPER for analyzing mean methylation of NR3C1-1F. Results: Adolescents in the NSSI group reported significantly more ACEs. The mean methylation level was about 3% in both groups with no significant group differences. Furthermore, no significant relation was found between ACE and methylation of NR3C1-1F, neither in the overall sample nor in the NSSI or HC group. Conclusion: Our results are contradictory to previous research showing an increased methylation in individuals with ACE. Regarding relations between methylation of NR3C1-1F and mental disorders, previous studies reported inconsistent findings. Our study points to NSSI being either unrelated to methylation of NR3C1-1F or to yet not identified moderators on relations between methylation of NR3C1-1F and engagement in NSSI during adolescence.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed.Arlington, VA: American Psychiatric Association; 2013.
Gillies D, Christou MA, Dixon AC, Featherston OJ, Rapti I, Garcia-Anguita A, et al. Prevalence and characteristics of self-harm in adolescents: meta-analyses of community-based studies 1990–2015. Child Adolesc Psychiatry. 2018 Oct 1;57(10):733–41.
Swannell SV, Martin GE, Page A, Hasking P, St John NJ. Prevalence of nonsuicidal self-injury in nonclinical samples: systematic review, meta-analysis and meta-regression. Suicide Life Threat Behav. 2014 Jun 1;44(3):273–303.
Winsper C, Hall J, Strauss VY, Wolke D. Aetiological pathways to Borderline Personality Disorder symptoms in early adolescence: childhood dysregulated behaviour, maladaptive parenting and bully victimisation. Borderline Personal Disord Emot Dysregul. 2017 Dec;4(1):10.
Linehan M. Cognitive behavior therapy of borderline personality disorder; 1993.
Taylor PJ, Jomar K, Dhingra K, Forrester R, Shahmalak U, Dickson JM. A meta-analysis of the prevalence of different functions of non-suicidal self-injury. J Affect Disord. 2018 Feb;227:759–69.
Brown RC, Heines S, Witt A, Braehler E, Fegert JM, Harsch D, et al. The impact of child maltreatment on non-suicidal self-injury: data from a representative sample of the general population. BMC Psychiatry. 2018 Jun;18(1):181.
Kaess M, Parzer P, Mattern M, Plener PL, Bifulco A, Resch F, et al. Adverse childhood experiences and their impact on frequency, severity, and the individual function of nonsuicidal self-injury in youth. Psychiatry Res. 2013 Apr;206(2–3):265–72.
Lang CM, Sharma-Patel K. The relation between childhood maltreatment and self-injury: a review of the literature on conceptualization and intervention. Trauma Violence Abuse. 2011 Jan;12(1):23–37.
Fox KR, Franklin JC, Ribeiro JD, Kleiman EM, Bentley KH, Nock MK. Meta-analysis of risk factors for nonsuicidal self-injury. Clin Psychol Rev. 2015 Dec;42:156–67.
Kaess M, Hooley JM, Klimes-Dougan B, Koenig J, Plener PL, Reichl C, et al. Advancing a temporal framework for understanding the biology of nonsuicidal self- injury: an expert review. Neurosci Biobehav Rev. 2021 Nov;130:228–39.
Kamin HS, Kertes DA. Cortisol and DHEA in development and psychopathology. Horm Behav. 2017 Mar;89:69–85.
Miller AB, Eisenlohr-Moul T, Glenn CR, Turner BJ, Chapman AL, Nock MK, et al. Does higher-than-usual stress predict nonsuicidal self-injury? Evidence from two prospective studies in adolescent and emerging adult females. J Child Psychol Psychiatry. 2019 Oct;60(10):1076–84.
Kaess M, Hille M, Parzer P, Maser-Gluth C, Resch F, Brunner R. Alterations in the neuroendocrinological stress response to acute psychosocial stress in adolescents engaging in nonsuicidal self-injury. Psychoneuroendocrinology. 2012 Jan;37(1):157–61.
Plener P, Zohsel K, Hohm E, Buchmann AF, Banaschewski T, Zimmermann US, et al. Lower cortisol level in response to a psychosocial stressor in young females with self-harm. Psychoneuroendocrinology. 2017;76:84–7.
Klimes-Dougan B, Begnel E, Almy B, Thai M, Schreiner MW, Cullen KR. Hypothalamic-pituitary-adrenal axis dysregulation in depressed adolescents with non-suicidal self-injury. Psychoneuroendocrinology. 2019 Apr;102:216–24.
Koenig J, Rinnewitz L, Warth M, Hillecke TK, Brunner R, Resch F, et al. Psychobiological response to pain in female adolescents with nonsuicidal self-injury. J Psychiatry Neurosci. 2017 May 1;42(3):189–99.
Reichl C, Heyer A, Brunner R, Parzer P, Völker JM, Resch F, et al. Hypothalamic-pituitary-adrenal axis, childhood adversity and adolescent nonsuicidal self-injury. Psychoneuroendocrinology. 2016 Dec;74:203–11.
Beauchaine TP, Crowell SE, Hsiao RC. Post-dexamethasone cortisol, self-inflicted injury, and suicidal ideation among depressed adolescent girls. J Abnorm Child Psychol. 2015 May;43(4):619–32.
Deighton S, Neville A, Pusch D, Dobson K. Biomarkers of adverse childhood experiences: a scoping review. Psychiatry Res. 2018 Nov;269:719–32.
Khoury JE, Bosquet Enlow M, Plamondon A, Lyons-Ruth K. The association between adversity and hair cortisol levels in humans: a meta-analysis. Psychoneuroendocrinology. 2019 May;103:104–17.
Kaess M, Whittle S, O’Brien-Simpson L, Allen NB, Simmons JG. Childhood maltreatment, pituitary volume and adolescent hypothalamic-pituitary-adrenal axis – evidence for a maltreatment-related attenuation. Psychoneuroendocrinology. 2018 Dec;98:39–45.
Weaver ICG. Epigenetic programming by maternal behavior and pharmacological intervention nature versus nurture: let’s call the whole thing off. Epigenetics. 2007 Jan 10;2(1):22–8.
NCBI [Internet]. Gene: NR3C1 nuclear receptor subfamily 3 group C member 1 [Homo sapiens (human)] [cited 2021 Apr 10]. Available from:
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009 Feb 22;12(3):342–8.
Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry. 2016 Jan;79(2):87–96.
Palma-Gudiel H, Córdova-Palomera A, Leza JC, Fañanás L. Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: a critical review. Neurosci Biobehav Rev. 2015 Aug;55:520–35.
Wadji DL, Tandon T, Ketcha Wanda GJM, Wicky C, Dentz A, Hasler G, et al. Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: a systematic review. Child Abuse Negl. 2021 Dec;122:105304.
Watkeys O, Kremerskothen K, Quidé Y, Fullerton J, Green M. Glucocorticoid receptor gene (NR3C1) DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation: a systematic review. Neurosci Biobehav Rev. 2018 Dec;95:85–122.
Martín-Blanco A, Ferrer M, Soler J, Salazar J, Vega D, Andión O, et al. Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder. J Psychiatr Res. 2014 Oct;57:34–40.
Kaess M, Ghinea D, Fischer-Waldschmidt G, Resch F. The outpatient clinic for adolescent risk-taking and self-harm behaviors (AtR!Sk): a pioneering approach of outpatient early detection and intervention of borderline personality disorder. Prax Kinderpsychol Kinderpsychiatr. 2017 Jul;66(6):404–22.
Fischer G, Ameis N, Parzer P, Plener PL, Groschwitz R, Vonderlin E, et al. The German version of the self-injurious thoughts and behaviors interview (SITBI-G): a tool to assess non-suicidal self-injury and suicidal behavior disorder. BMC Psychiatry. 2014;14:265.
Kaess M, Parzer P, Mattern M, Resch F, Bifulco A, Brunner R. Childhood Experiences of Care and Abuse (CECA): validierung der deutschen Version von Fragebogen und korrespondierendem Interview sowie Ergebnisse einer Untersuchung von Zusammenhängen belastender Kindheitserlebnisse mit suizidalen Verhaltensweisen. Z Kinder Jugendpsychiatr Psychother. 2011 Jul;39(4):243–52.
Sheehan D, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, et al. Reliability and validity of the Mini international neuropsychiatric interview for children and adolescents (MINI-KID). J Clin Psychiatry. 2010 Mar;71(3):313–26.
Frydrich T, Renneberg B, Schmitz B, Wittchen HU. SKID II. Strukturiertes Klinisches Interview für DSM-IV, Achse II: persönlichkeitsstörungen. Interviewheft. Eine deutschspeachige, erw. Bearb. d. amerikanischen Originalversion d. SKID-II von: M.B. First, R.L. Spitzer, M. Gibbon, J.B.W. Williams, L. Benjamin, (Version 3/96). [Internet]. Göttingen: Hogrefe.; 1997. Available from:
Suchiman HED, Slieker RC, Kremer D, Slagboom PE, Heijmans BT, Tobi EW. Design, measurement and processing of region-specific DNA methylation assays: the mass spectrometry-based method EpiTYPER. Front Genet. 2015 Sep 17;6:287.
Nantharat M, Wanitchanon T, Amesbutr M, Tammachote R, Praphanphoj V. Glucocorticoid receptor gene (NR3C1) promoter is hypermethylated in Thai females with major depressive disorder. Genet Mol Res. 2015;14(4):19071–9.
Perroud N, Paoloni-Giacobino A, Prada P, Olié E, Salzmann A, Nicastro R, et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry. 2011 Dec;1(12):e59.
Alexander N, Kirschbaum C, Wankerl M, Stauch BJ, Stalder T, Steudte-Schmiedgen S, et al. Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity. Psychoneuroendocrinology. 2018 Apr;90:68–75.
Parent J, Parade SH, Laumann LE, Ridout KK, Yang BZ, Marsit CJ, et al. Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: the role of child maltreatment. Dev Psychopathol. 2017 Dec;29(5):1635–48.
Schür RR, van Leeuwen JMC, Houtepen LC, Joels M, Kahn RS, Boks MP, et al. Glucocorticoid receptor exon 1F methylation and the cortisol stress response in health and disease. Psychoneuroendocrinology. 2018 Nov;97:182–9.
Li M, D’Arcy C, Li X, Zhang T, Joober R, Meng X. What do DNA methylation studies tell us about depression? A systematic review. Transl Psychiatry. 2019 Dec;9(1):68.
Yehuda R, Flory JD, Bierer LM, Henn-Haase C, Lehrner A, Desarnaud F, et al. Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry. 2015 Feb;77(4):356–64.
Flasbeck V, Brüne M. Association between childhood maltreatment, psychopathology and DNA methylation of genes involved in stress regulation: evidence from a study in Borderline Personality Disorder. PLOS ONE. 2021 Mar 11;16(3):e0248514.
Shinozaki G, Braun P, Hing B, Nagahama Y, Gaul L, Heinzman J, et al. 57. Genome-wide DNA methylation comparison by illumina epic array between live human brain and peripheral tissues within individuals. Biol Psychiatry. 2017 May;81(10):S24.
Park C, Rosenblat JD, Brietzke E, Pan Z, Lee Y, Cao B, et al. Stress, epigenetics and depression: a systematic review. Neurosci Biobehav Rev. 2019 Jul;102:139–52.
Miller O, Shakespeare-Finch J, Bruenig D, Mehta D. DNA methylation of NR3C1 and FKBP5 is associated with posttraumatic stress disorder, posttraumatic growth, and resilience. Psychol Trauma. 2020 Oct;12(7):750–5.
Theda C, Hwang SH, Czajko A, Loke YJ, Leong P, Craig JM. Quantitation of the cellular content of saliva and buccal swab samples. Sci Rep. 2018 Dec;8:6944.
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