Epigenetic Modifications in Borderline Personality Disorder

  • Reinhard H. DammannEmail author
  • Gerhard W. Dammann
Part of the Epigenetics and Human Health book series (EHH)


Borderline personality disorder (BPD) is a complex psychic disease with an increased importance in the last years. While the diagnosis and therapy are well established, little is known on the pathogenesis of BPD. Epigenetic alterations are a hallmark for abnormal gene expression and could be involved in the etiology of BPD. These epigenetic changes are mainly classified into altered histone modifications and DNA methylation. Here, we summarize recent findings on epigenetic alterations in BPD. Significant aberrant DNA methylation of serotonin receptor 2A (HTR2A), monoamine oxidase A and B (MAOA and MAOB), glucocorticoid receptor (GR/NR3C1), brain derived neurotrophic factor (BDNF), amyloid beta precursor protein-binding family A member 2 and 3 (APBA2 and APBA3), KCNQ1, MCF2, and ninjurin 2 (NINJ2) has been reported. DNA methylation changes range between 1.1- and 1.5-fold increased methylation in the blood of BPD subjects. Especially, GR/NR3C1 methylation was positively associated with childhood maltreatment and clinical severity in BPD. These data may provide new insights into epigenetic mechanisms underlying the pathogenesis of borderline personality disorder.


Borderline personality disorder Epigenetics DNA methylation 


  1. Abdolmaleky HM, Smith CL, Zhou JR, Thiagalingam S (2008) Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Methods Mol Biol 448:187–212CrossRefPubMedGoogle Scholar
  2. Agius M, Lee J, Gardner J, Wotherspoon D (2012) Bipolar II disorder and borderline personality disorder – co-morbidity or spectrum? Psychiatr Danub 24(Suppl 1):S197–S201PubMedGoogle Scholar
  3. Alisch RS, Chopra P, Fox AS et al (2014) Differentially methylated plasticity genes in the amygdala of young primates are linked to anxious temperament, an at risk phenotype for anxiety and depressive disorders. J Neurosci 34:15548–15556. doi: 10.1523/JNEUROSCI.3338-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  4. APA (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
  5. Bibikova M, Lin Z, Zhou L et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16:383–393CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213CrossRefPubMedGoogle Scholar
  7. Clarkin JF, Levy KN, Dammann G (2004) An object-relations approach to the treatment of borderline patients. In: Kaslow FW, Magnavita JJ (eds) Comprehensive handbook of psychotherapy, vol 1, Psychodynamic/object relations. Wiley, New York, pp 239–252Google Scholar
  8. Dammann G (2003) Borderline personality disorder and theory of mind: an evolutionary perspective. In: Brüne M, Ribbert H, Schiefenhövel W (eds) The social brain: evolution and pathology. Wiley, Chichester, pp 373–417CrossRefGoogle Scholar
  9. Dammann G (2004) Differential diagnosis between borderline personality disorder and schizophrenic illness in adolescents with psychotic symptoms. In: Bürgin D, Meng H (eds) Childhood and adolescent psychosis. Karger, Basel, pp 94–108CrossRefGoogle Scholar
  10. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25:315–319CrossRefPubMedGoogle Scholar
  11. Dammann G, Teschler S, Haag T, Altmuller F, Tuczek F, Dammann RH (2011) Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder. Epigenetics 6:1454–1462. doi: 10.4161/Epi.6.12.18363 CrossRefPubMedGoogle Scholar
  12. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298CrossRefPubMedGoogle Scholar
  13. Famularo R, Kinscherff R, Fenton T (1991) Posttraumatic stress disorder among children clinically diagnosed as borderline personality disorder. J Nerv Ment Dis 179:428–431CrossRefPubMedGoogle Scholar
  14. Goldman SJ, D’Angelo EJ, DeMaso DR, Mezzacappa E (1992) Physical and sexual abuse histories among children with borderline personality disorder. Am J Psychiatry 149:1723–1726CrossRefPubMedGoogle Scholar
  15. Grant BF, Chou SP, Goldstein RB et al (2008) Prevalence, correlates, disability, and comorbidity of DSM-IV borderline personality disorder: results from the wave 2 national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry 69:533–545CrossRefPubMedPubMedCentralGoogle Scholar
  16. Gremaud-Heitz D, Riemenschneider A, Walter M, Sollberger D, Kuchenhoff J, Dammann G (2014) Comorbid atypical depression in borderline personality disorder is common and correlated with anxiety-related psychopathology. Compr Psychiatry 55:650–656. doi: 10.1016/j.comppsych.2013.11.021 CrossRefPubMedGoogle Scholar
  17. Groleau P, Joober R, Israel M, Zeramdini N, DeGuzman R, Steiger H (2014) Methylation of the dopamine D2 receptor (DRD2) gene promoter in women with a bulimia-spectrum disorder: associations with borderline personality disorder and exposure to childhood abuse. J Psychiatr Res 48:121–127. doi: 10.1016/j.jpsychires.2013.10.003 CrossRefPubMedGoogle Scholar
  18. Gunnar M, Quevedo K (2007) The neurobiology of stress and development. Annu Rev Psychol 58:145–173CrossRefPubMedGoogle Scholar
  19. Herman JL, Perry JC, van der Kolk BA (1989) Childhood trauma in borderline personality disorder. Am J Psychiatry 146:490–495CrossRefPubMedGoogle Scholar
  20. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kaffman A, Meaney MJ (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry 48:224–244CrossRefPubMedGoogle Scholar
  22. Leichsenring F, Leibing E, Kruse J, New AS, Leweke F (2011) Borderline personality disorder. Lancet 377:74–84CrossRefPubMedGoogle Scholar
  23. Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M (2004) Borderline personality disorder. Lancet 364:453–461CrossRefPubMedGoogle Scholar
  24. Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448. doi: 10.1016/j.molcel.2007.07.015 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Martin-Blanco A, Ferrer M, Soler J et al (2014) Association between methylation of the glucocorticoid receptor gene, childhood maltreatment, and clinical severity in borderline personality disorder. J Psychiatr Res 57:34–40. doi: 10.1016/j.jpsychires.2014.06.011 CrossRefPubMedGoogle Scholar
  26. McGowan PO, Sasaki A, D’Alessio AC et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348CrossRefPubMedPubMedCentralGoogle Scholar
  27. McGowan PO, Suderman M, Sasaki A, Huang TC, Hallett M, Meaney MJ, Szyf M (2011) Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 6:e14739CrossRefPubMedPubMedCentralGoogle Scholar
  28. Mitchelmore C, Gede L (2014) Brain derived neurotrophic factor: epigenetic regulation in psychiatric disorders. Brain Res 1586:162–172. doi: 10.1016/j.brainres.2014.06.037 CrossRefPubMedGoogle Scholar
  29. Paquette AG, Marsit CJ (2014) The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. J Cell Biochem 115:2065–2072. doi: 10.1002/jcb.24883 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Paris J, Zweig-Frank H, Guzder J (1994) Risk factors for borderline personality in male outpatients. J Nerv Ment Dis 182:375–380CrossRefPubMedGoogle Scholar
  31. Perroud N, Paoloni-Giacobino A, Prada P et al (2011) 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 1:e59. doi: 10.1038/tp.2011.60 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Perroud N, Salzmann A, Prada P et al (2013) Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene. Transl Psychiatry 3:e207. doi: 10.1038/tp.2012.140 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Prados J, Stenz L, Courtet P et al (2015) Borderline personality disorder and childhood maltreatment: a genome-wide methylation analysis. Genes Brain Behav. doi: 10.1111/gbb.12197 PubMedGoogle Scholar
  34. Puglia MH, Lillard TS, Morris JP, Connelly JJ (2015) Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proc Natl Acad Sci USA 112:3308–3313. doi: 10.1073/pnas.1422096112 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ripoll LH, Snyder R, Steele H, Siever LJ (2013) The neurobiology of empathy in borderline personality disorder. Curr Psychiatry Rep 15:344. doi: 10.1007/s11920-012-0344-1 CrossRefPubMedGoogle Scholar
  36. Sandoval J, Heyn HA, Moran S, Serra-Musach J, Pujana MA, Bibikova M, Esteller M (2011) Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6:692–702CrossRefPubMedGoogle Scholar
  37. Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103:1412–1417CrossRefPubMedPubMedCentralGoogle Scholar
  38. Siever LJ, Torgersen S, Gunderson JG, Livesley WJ, Kendler KS (2002) The borderline diagnosis III: identifying endophenotypes for genetic studies. Biol Psychiatry 51:964–968CrossRefPubMedGoogle Scholar
  39. Silk KR, Lee S, Hill EM, Lohr NE (1995) Borderline personality disorder symptoms and severity of sexual abuse. Am J Psychiatry 152:1059–1064CrossRefPubMedGoogle Scholar
  40. Sillivan SE, Vaissiere T, Miller CA (2015) Neuroepigenetic regulation of pathogenic memories. Neuroepigenetics 1:28–33. doi: 10.1016/j.nepig.2014.10.003 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Skodol AE, Gunderson JG, McGlashan TH et al (2002a) Functional impairment in patients with schizotypal, borderline, avoidant, or obsessive-compulsive personality disorder. Am J Psychiatry 159:276–283CrossRefPubMedGoogle Scholar
  42. Skodol AE, Siever LJ, Livesley WJ, Gunderson JG, Pfohl B, Widiger TA (2002b) The borderline diagnosis II: biology, genetics, and clinical course. Biol Psychiatry 51:951–963CrossRefPubMedGoogle Scholar
  43. Soloff PH, Lynch KG, Kelly TM (2002) Childhood abuse as a risk factor for suicidal behavior in borderline personality disorder. J Pers Disord 16:201–214CrossRefPubMedGoogle Scholar
  44. Steele H, Siever L (2010) An attachment perspective on borderline personality disorder: advances in gene-environment considerations. Curr Psychiatry Rep 12:61–67. doi: 10.1007/s11920-009-0091-0 CrossRefPubMedGoogle Scholar
  45. Steiger H, Labonte B, Groleau P, Turecki G, Israel M (2013) Methylation of the glucocorticoid receptor gene promoter in bulimic women: associations with borderline personality disorder, suicidality, and exposure to childhood abuse. Int J Eat Disord 46:246–255. doi: 10.1002/eat.22113 CrossRefPubMedGoogle Scholar
  46. Teschler S, Bartkuhn M, Kunzel N, Schmidt C, Kiehl S, Dammann G, Dammann R (2013) Aberrant methylation of gene associated CpG sites occurs in borderline personality disorder. PLoS ONE 8:e84180. doi: 10.1371/journal.pone.0084180 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Thaler L, Gauvin L, Joober R et al (2014) Methylation of BDNF in women with bulimic eating syndromes: associations with childhood abuse and borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry 54:43–49. doi: 10.1016/j.pnpbp.2014.04.010 CrossRefPubMedGoogle Scholar
  48. Toda H, Boku S, Nakagawa S et al (2014) Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala. PLoS ONE 9:e97421. doi: 10.1371/journal.pone.0097421 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Torgersen S, Kringlen E, Cramer V (2001) The prevalence of personality disorders in a community sample. Arch Gen Psychiatry 58:590–596CrossRefPubMedGoogle Scholar
  50. Torgersen S, Czajkowski N, Jacobson K, Reichborn-Kjennerud T, Roysamb E, Neale MC, Kendler KS (2008) Dimensional representations of DSM-IV cluster B personality disorders in a population-based sample of Norwegian twins: a multivariate study. Psychol Med 38:1617–1625CrossRefPubMedGoogle Scholar
  51. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367CrossRefPubMedGoogle Scholar
  52. Tsuji M, Miyagawa K, Takeda H (2014) Epigenetic regulation of resistance to emotional stress: possible involvement of 5-HT1A receptor-mediated histone acetylation. J Pharmacol Sci 125:347–354CrossRefPubMedGoogle Scholar
  53. Turecki G (2014) The molecular bases of the suicidal brain. Nat Rev Neurosci 15:802–816. doi: 10.1038/nrn3839 CrossRefPubMedGoogle Scholar
  54. van Vliet J, Oates NA, Whitelaw E (2007) Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 64:1531–1538CrossRefPubMedGoogle Scholar
  55. Waller G (1994) Childhood sexual abuse and borderline personality disorder in the eating disorders. Child Abuse Negl 18:97–101CrossRefPubMedGoogle Scholar
  56. Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schubeler D (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39:457–466CrossRefPubMedGoogle Scholar
  57. Widiger TA, Weissman MM (1991) Epidemiology of borderline personality disorder. Hosp Community Psychiatry 42:1015–1021PubMedGoogle Scholar
  58. Zanarini MC, Frankenburg FR, Hennen J, Reich DB, Silk KR (2006) Prediction of the 10-year course of borderline personality disorder. Am J Psychiatry 163:827–832CrossRefPubMedGoogle Scholar
  59. Zimmerman M (1994) Diagnosing personality disorders. A review of issues and research methods. Arch Gen Psychiatry 51:225–245CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Institute for GeneticsJustus-Liebig-UniversityGiessenGermany
  2. 2.Psychiatric Services of ThurgoviaAcademic Teaching Hospital of the Medical University of SalzburgMünsterlingenSwitzerland

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