The association between childhood maltreatment and empathic perspective taking is moderated by the 5-HTT linked polymorphic region: Another example of “differential susceptibility”

Autoři: Vera Flasbeck aff001;  Dirk Moser aff002;  Johanna Pakusch aff003;  Robert Kumsta aff002;  Martin Brüne aff001
Působiště autorů: LWL University Hospital, Department of Psychiatry, Psychotherapy and Preventive Medicine, Division of Social Neuropsychiatry and Evolutionary Medicine, Ruhr-University Bochum, Bochum, Germany aff001;  Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Bochum, Germany aff002;  Department of General Zoology and Neurobiology, Ruhr-University Bochum, Bochum, Germany aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Previous research has suggested that the short (S)-allele of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) may confer “differential susceptibility” to environmental impact with regard to the expression of personality traits, depressivity and impulsivity. However, little is known about the role of 5-HTTLPR concerning the association between childhood adversity and empathy. Here, we analyzed samples of 137 healthy participants and 142 individuals diagnosed with borderline personality disorder (BPD) focusing on the 5-HTTLPR genotype (S/L-carrier) and A/G SNP (rs25531), in relation to childhood maltreatment and empathy traits. Whereas no between-group difference in 5-HTTLPR genotype distribution emerged, the S-allele selectively moderated the impact of childhood maltreatment on empathic perspective taking, whereby low scores in childhood trauma were associated with superior perspective taking. In contrast, L-homozygotes seemed to be largely unresponsive to variation in environmental conditions in relation to empathy, suggesting that the S-allele confers “differential susceptibility”. Moreover, a moderation analysis and tests for differential susceptibility yielded similar results when transcriptional activity of the serotonin transporter gene was taken into account. In conclusion, our findings suggest that the S-allele of the 5-HTTLPR is responsive to early developmental contingencies for “better and worse”, i.e. conferring genetic plasticity, especially with regard to processes involving emotional resonance.

Klíčová slova:

Behavior – Depression – DNA transcription – Emotions – Personality disorders – Psychological stress – Psychometrics – Serotonin


1. Gonzalez-Liencres C, Shamay-Tsoory SG, Brüne M. Towards a neuroscience of empathy: ontogeny, phylogeny, brain mechanisms, context and psychopathology. Neurosci Biobehav Rev 2013; 37(8):1537–48. doi: 10.1016/j.neubiorev.2013.05.001 23680700

2. Singer T. The neuronal basis and ontogeny of empathy and mind reading: review of literature and implications for future research. Neurosci Biobehav Rev 2006; 30(6):855–63. doi: 10.1016/j.neubiorev.2006.06.011 16904182

3. Singer T, Lamm C. The social neuroscience of empathy. Ann N Y Acad Sci 2009; 1156:81–96. doi: 10.1111/j.1749-6632.2009.04418.x 19338504

4. Dziobek I, Rogers K, Fleck S, Bahnemann M, Heekeren HR, Wolf OT et al. Dissociation of cognitive and emotional empathy in adults with Asperger syndrome using the Multifaceted Empathy Test (MET). J Autism Dev Disord 2008; 38(3):464–73. doi: 10.1007/s10803-007-0486-x 17990089

5. Smith A. The empathy imbalance hypothesis of autism: a theoretical approach to cognitive and emotional empathy in autistic development. the Psychological record 2009; 59(3):489–510. Available from: URL:

6. Bora E, Gokcen S, Veznedaroglu B. Empathic abilities in people with schizophrenia. Psychiatry Res 2008; 160(1):23–9. doi: 10.1016/j.psychres.2007.05.017 18514324

7. Haker H, Rössler W. Empathy in schizophrenia: impaired resonance. Eur Arch Psychiatry Clin Neurosci 2009; 259(6):352–61. doi: 10.1007/s00406-009-0007-3 19377866

8. Blair RJR. Responding to the emotions of others: dissociating forms of empathy through the study of typical and psychiatric populations. Conscious Cogn 2005; 14(4):698–718. doi: 10.1016/j.concog.2005.06.004 16157488

9. Dinsdale N, Crespi BJ. The borderline empathy paradox: evidence and conceptual models for empathic enhancements in borderline personality disorder. J Pers Disord 2013; 27(2):172–95. doi: 10.1521/pedi.2013.27.2.172 23514182

10. Harari H, Shamay-Tsoory SG, Ravid M, Levkovitz Y. Double dissociation between cognitive and affective empathy in borderline personality disorder. Psychiatry Res 2010; 175(3):277–9. doi: 10.1016/j.psychres.2009.03.002 20045198

11. Niedtfeld I. Experimental investigation of cognitive and affective empathy in borderline personality disorder: Effects of ambiguity in multimodal social information processing. Psychiatry Res 2017; 253:58–63. doi: 10.1016/j.psychres.2017.03.037 28351003

12. Preissler S, Dziobek I, Ritter K, Heekeren HR, Roepke S. Social Cognition in Borderline Personality Disorder: Evidence for Disturbed Recognition of the Emotions, Thoughts, and Intentions of others. Front Behav Neurosci 2010; 4:182. doi: 10.3389/fnbeh.2010.00182 21151817

13. Wingenfeld K, Duesenberg M, Fleischer J, Roepke S, Dziobek I, Otte C et al. Psychosocial stress differentially affects emotional empathy in women with borderline personality disorder and healthy controls. Acta Psychiatr Scand 2018; 137(3):206–15. doi: 10.1111/acps.12856 29417987

14. Flasbeck V, Enzi B, Brüne M. Altered Empathy for Psychological and Physical Pain in Borderline Personality Disorder. J Pers Disord 2017; 31(5):689–708. doi: 10.1521/pedi_2017_31_276 28072040

15. Carver CS, Johnson SL, Joormann J. Two-Mode Models of Self-Regulation as a Tool for Conceptualizing Effects of the Serotonin System in Normal Behavior and Diverse Disorders. Curr Dir Psychol Sci 2009; 18(4):195–9. doi: 10.1111/j.1467-8721.2009.01635.x 20161026

16. Spoont MR. Modulatory role of serotonin in neural information processing: implications for human psychopathology. Psychol Bull 1992; 112(2):330–50. doi: 10.1037/0033-2909.112.2.330 1454898

17. Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002; 7(1):118–22. doi: 10.1038/ 11803458

18. Champoux M, Bennett A, Shannon C, Higley JD, Lesch KP, Suomi SJ. Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol Psychiatry 2002; 7(10):1058–63. doi: 10.1038/ 12476320

19. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297(5580):400–3. doi: 10.1126/science.1071829 12130784

20. Kenna GA, Roder-Hanna N, Leggio L, Zywiak WH, Clifford J, Edwards S et al. Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy. Pharmgenomics Pers Med 2012; 5:19–35. doi: 10.2147/PGPM.S23462 23226060

21. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274(5292):1527–31. doi: 10.1126/science.274.5292.1527 8929413

22. Lesch KP, Mössner R. Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998; 44(3):179–92. doi: 10.1016/s0006-3223(98)00121-8 9693390

23. Wagner S, Baskaya O, Lieb K, Dahmen N, Tadic A. The 5-HTTLPR polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder. J Psychiatr Res 2009; 43(13):1067–72. doi: 10.1016/j.jpsychires.2009.03.004 19358998

24. Beevers CG, Wells TT, Ellis AJ, McGeary JE. Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli. J Abnorm Psychol 2009; 118(3):670–81. doi: 10.1037/a0016198 19685963

25. Beevers CG, Marti CN, Lee H-J, Stote DL, Ferrell RE, Hariri AR et al. Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information. J Abnorm Psychol 2011; 120(1):187–97. doi: 10.1037/a0022125 21319930

26. Fox E, Ridgewell A, Ashwin C. Looking on the bright side: biased attention and the human serotonin transporter gene. Proc Biol Sci 2009; 276(1663):1747–51. doi: 10.1098/rspb.2008.1788 19324793

27. Gyurak A, Haase CM, Sze J, Goodkind MS, Coppola G, Lane J et al. The effect of the serotonin transporter polymorphism (5-HTTLPR) on empathic and self-conscious emotional reactivity. Emotion 2013; 13(1):25–35. doi: 10.1037/a0029616 22906085

28. Osinsky R, Reuter M, Kupper Y, Schmitz A, Kozyra E, Alexander N et al. Variation in the serotonin transporter gene modulates selective attention to threat. Emotion 2008; 8(4):584–8. doi: 10.1037/a0012826 18729589

29. Way BM, Taylor SE. The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biol Psychiatry 2010; 67(5):487–92. doi: 10.1016/j.biopsych.2009.10.021 20006325

30. Amad A, Ramoz N, Thomas P, Jardri R, Gorwood P. Genetics of borderline personality disorder: systematic review and proposal of an integrative model.

31. Risch N, Herrell R, Lehner T, Liang K-Y, Eaves L, Hoh J et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009; 301(23):2462–71. doi: 10.1001/jama.2009.878 19531786

32. Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C et al. Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders. Am J Med Genet 2002; 114(4):361–9. doi: 10.1002/ajmg.10356 11992558

33. Noskova T, Pivac N, Nedic G, Kazantseva A, Gaysina D, Faskhutdinova G et al. Ethnic differences in the serotonin transporter polymorphism (5-HTTLPR) in several European populations. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2008; 32(7):1735–9. doi: 10.1016/j.pnpbp.2008.07.012 18700161

34. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Brady K et al. Interactive Effect of Stressful Life Events and the Serotonin Transporter 5-HTTLPR Genotype on Posttraumatic Stress Disorder Diagnosis in 2 Independent Populations. PSYCH 2009; 66(11):1201–9.

35. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005; 29(1):8–16. doi: 10.1097/01.alc.0000150008.68473.62 15654286

36. Wendland JR, Martin BJ, Kruse MR, Lesch K-P, Murphy DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 2006; 11(3):224–6. doi: 10.1038/ 16402131

37. Wüst S, Kumsta R, Treutlein J, Frank J, Entringer S, Schulze TG et al. Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion. Psychoneuroendocrinology 2009; 34(7):972–82. doi: 10.1016/j.psyneuen.2009.01.011 19249159

38. Kohen R, Cain KC, Mitchell PH, Becker K, Buzaitis A, Millard SP et al. Association of Serotonin Transporter Gene Polymorphisms With Poststroke Depression. PSYCH 2008; 65(11):1296–302.

39. Brüne M, Belsky J, Fabrega H, Feierman HR, Gilbert P, Glantz K et al. The crisis of psychiatry—insights and prospects from evolutionary theory. World Psychiatry 2012; 11(1):55–7. doi: 10.1016/j.wpsyc.2012.01.009 22295011

40. Monroe SM, Simons AD. Diathesis-stress theories in the context of life stress research: implications for the depressive disorders. Psychol Bull 1991; 110(3):406–25. doi: 10.1037/0033-2909.110.3.406 1758917

41. Boyce WT, Ellis BJ. Biological sensitivity to context: I. An evolutionary-developmental theory of the origins and functions of stress reactivity. Dev Psychopathol 2005; 17(2):271–301. doi: 10.1017/s0954579405050145 16761546

42. Bakermans-Kranenburg MJ, van Ijzendoorn MH. Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Soc Cogn Affect Neurosci 2008; 3(2):128–34. doi: 10.1093/scan/nsn004 19015103

43. Belsky J, Pluess M. Beyond diathesis stress: differential susceptibility to environmental influences. Psychol Bull 2009; 135(6):885–908. doi: 10.1037/a0017376 19883141

44. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301(5631):386–9. doi: 10.1126/science.1083968 12869766

45. Clarke H, Flint J, Attwood AS, Munafo MR. Association of the 5- HTTLPR genotype and unipolar depression: a meta-analysis. Psychol Med 2010; 40(11):1767–78. doi: 10.1017/S0033291710000516 20380781

46. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 2011; 68(5):444–54. doi: 10.1001/archgenpsychiatry.2010.189 21199959

47. Culverhouse RC, Saccone NL, Horton AC, Ma Y, Anstey KJ, Banaschewski T et al. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol Psychiatry 2018; 23(1):133–42. doi: 10.1038/mp.2017.44 28373689

48. Pluess M, Belsky J, Way BM, Taylor SE. 5-HTTLPR moderates effects of current life events on neuroticism: differential susceptibility to environmental influences. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(6):1070–4. doi: 10.1016/j.pnpbp.2010.05.028 20573579

49. Kuepper Y, Wielpuetz C, Alexander N, Mueller E, Grant P, Hennig J. 5-HTTLPR S-allele: a genetic plasticity factor regarding the effects of life events on personality? Genes Brain Behav 2012; 11(6):643–50. doi: 10.1111/j.1601-183X.2012.00783.x 22420614

50. Association AP. Diagnostic and statistical manual of mental disorders (DSM-5®): American Psychiatric Pub; 2013.

51. Lehrl S, Merz J, Burkhard G, Fischer S. Mehrfachwahl-Wortschatz-Intelligenztest (MWT-A). Manual. Göttingen: Hogrefe; 1991.

52. Davis MH. Measuring individual differences in empathy: Evidence for a multidimensional approach. Journal of Personality and Social Psychology 1983; 44(1):113–26.

53. Paulus C. Saarbrücker Persönlichkeits-Fragebogen (SPF)[[Saarbrücken personality questionnaire]. Based on the interpersonal reactivity index (IRI) including new items (V3. 0); 2006.

54. Wolf OT, Schulte JM, Drimalla H, Hamacher-Dang TC, Knoch D, Dziobek I. Enhanced emotional empathy after psychosocial stress in young healthy men. Stress 2015; 18(6):631–7. doi: 10.3109/10253890.2015.1078787 26365125

55. Nomura K, Akai S. Empathy with fictional stories: reconsideration of the fantasy scale of the interpersonal reactivity index. Psychol Rep 2012; 110(1):304–14. doi: 10.2466/ 22489396

56. Klinitzke G, Romppel M, Häuser W, Brähler E, Glaesmer H. Die deutsche Version des Childhood Trauma Questionnaire (CTQ)–psychometrische Eigenschaften in einer bevölkerungsrepräsentativen Stichprobe. Psychother Psych Med 2012; 62(02):47–51.

57. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–71. doi: 10.1001/archpsyc.1961.01710120031004 13688369

58. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3):1215. doi: 10.1093/nar/16.3.1215 3344216

59. Faul F, Erdfelder E, Buchner A, Lang A-G. Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behavior Research Methods 2009; 41(4):1149–60. doi: 10.3758/BRM.41.4.1149 19897823

60. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J et al. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 2000; 96(2):202–16. doi: 10.1002/(sici)1096-8628(20000403)96:2<202::aid-ajmg16>;2-j 10893498

61. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 2005; 8(6):828–34. doi: 10.1038/nn1463 15880108

62. Stoltenberg SF, Christ CC, Carlo G. Afraid to help: social anxiety partially mediates the association between 5-HTTLPR triallelic genotype and prosocial behavior. Soc Neurosci 2013; 8(5):400–6. doi: 10.1080/17470919.2013.807874 23789884

63. Hayes AF. Introduction to mediation, moderation, and conditional process analysis: A regression-based approach. New York: The Guilford Press; 2013. (Methodology in the social sciences).

64. Belsky J, Bakermans-Kranenburg MJ, van Ijzendoorn MH. For Better and For Worse: Differential Susceptibility to Environmental Influences. Curr Dir Psychol Sci 2007; 16(6):300–4.

65. Flasbeck V, Moser D, Kumsta R, Brüne M. The OXTR Single-Nucleotide Polymorphism rs53576 Moderates the Impact of Childhood Maltreatment on Empathy for Social Pain in Female Participants: Evidence for Differential Susceptibility. Front Psychiatry 2018; 9:359. doi: 10.3389/fpsyt.2018.00359 30135663

66. Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R. Vulnerability genes or plasticity genes? Mol Psychiatry 2009; 14(8):746–54. doi: 10.1038/mp.2009.44 19455150

67. Owens M, Goodyer IM, Wilkinson P, Bhardwaj A, Abbott R, Croudace T et al. 5-HTTLPR and early childhood adversities moderate cognitive and emotional processing in adolescence. PLoS One 2012; 7(11):e48482. doi: 10.1371/journal.pone.0048482 23209555

68. Gotlib IH, Joormann J, Minor KL, Hallmayer J. HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 2008; 63(9):847–51. doi: 10.1016/j.biopsych.2007.10.008 18005940

69. Markus CR, Raedt R de. Differential effects of 5-HTTLPR genotypes on inhibition of negative emotional information following acute stress exposure and tryptophan challenge. Neuropsychopharmacology 2011; 36(4):819–26. doi: 10.1038/npp.2010.221 21150915

70. Booij L, Wang D, Lévesque ML, Tremblay RE, Szyf M. Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress–diathesis model of depression. Philosophical Transactions of the Royal Society B: Biological Sciences 2013; 368(1615):20120251.

71. Steiger H, Richardson J, Joober R, Gauvin L, Israel M, Bruce KR et al. The 5HTTLPR polymorphism, prior maltreatment and dramatic-erratic personality manifestations in women with bulimic syndromes. J Psychiatry Neurosci 2007; 32(5):354–62. 17823651

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