Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population

  • Xenia GondaEmail author
  • Konstantinos N. Fountoulakis
  • Gabriella Juhasz
  • Zoltan Rihmer
  • Judit Lazary
  • Andras Laszik
  • Hagop S. Akiskal
  • Gyorgy Bagdy



Research concerning the genetic background of traits, temperaments and psychiatric disorders has been rapidly expanding. One of the most frequently studied genetic polymorphisms in the background of psychological and psychiatric phenomena is the 5-HTTLPR polymorphism of the serotonin transporter gene which has earlier been found to be associated with neuroticism and neuroticism-related traits and disorders. However, both the neuroticism trait and psychiatric disorders are complex and composed of several subfacets. The aim of our study was to investigate the association of the 5-HTTLPR polymorphism with several smaller, distinct and better characterisable phenomena related to the neuroticism trait.


169 healthy females participated in the study. All participants completed the Buss–Durkee Hostility Inventory (BDHI), the State-Trait Anxiety Inventory (STAI), The Zung Self-rating Depression Scale (ZSDS), the Beck Hopelessness Scale, the SCL-51, the Temperament and Character Inventory (TCI) and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) questionnaire. All subjects were genotyped for the 5-HTTLPR using PCR. Data were analysed with ANOVA and MANCOVA with age as a covariate.


We found that the presence of the s allele was significantly associated with anxiety, depression, hopelessness, guilt, hostility, aggression, presence of neurotic symptoms, self-directedness and affective temperaments carrying a depressive component even when controlling for age.


Our study is the first that confirms that traits and characteristics related to neuroticism, such as increased anxiety, depression, hopelessness, somatization, feeling of guilt, hostility, aggression, lack of self-directedness and affective temperament are consistently and independently associated with the 5-HTTLPR polymorphism of the serotonin transporter gene. Our study therefore suggests that neuroticism can be considered a unified construct not only from a phenotypical but also from a genetic point of view and 5HTTLPR can be considered one component of its polygenic background. Our results thus yield further insight into the role of the 5-HTTLPR in the background of neuroticism and neuroticism-related psychiatric disorders.


5-HTTLPR polymorphism neuroticism affective temperaments 



These studies were supported by the Sixth Framework Programme of the EU, LSHM-CT-2004-503474, the Ministry of Welfare Research Grant 460/2006, the Hungarian Research Fund Grants 022256/1997 and 032398/2000 and the PhD Fellowship Program of the Semmelweis University, Ministry of Culture and Education, Hungary. The authors wish to thank Sandor Rozsa and Eszter Molnár for their help and advice concerning the manuscript.


  1. 1.
    Akiskal HS (1996) The temperamental foundations of mood disorders. In: Mundt CH (ed) Factors in the origin and course of affective disorders. Gaskell, London, pp 3–30Google Scholar
  2. 2.
    Akiskal HS (1995) Toward a temperament-based approach to depression: implications for neurobiologic research. Adv Biochem Psychopharmacol 49:99–112PubMedGoogle Scholar
  3. 3.
    Akiskal HS, Akiskal KK (1992) Cyclothymic, hyperthymic and depressive temperaments as subaffective variants of mood disorders. In: Tasman A, Riba MB (eds) Annual reviews 11. American Psychiatric Press, Washington, DC, pp 43–62Google Scholar
  4. 4.
    Akiskal HS, Akiskal KK (2005) Special issue. TEMPS: temperament evaluation of Memphis, Pisa, Paris and San Diego. J Affect Disord 85:1–242PubMedCrossRefGoogle Scholar
  5. 5.
    Akiskal HS, Kilzieh N, Maser JD, Clayton PJ, Schettler PJ, Traci Shea M, Endicott J, Scheftner W, Hirschfeld RM, Keller MB (2006) The distinct temperament profiles of bipolar I, bipolar II and unipolar patients. J Affect Disord 92:19–33PubMedCrossRefGoogle Scholar
  6. 6.
    Akiskal HS, Mallya G (1987) Criteria for the “soft” bipolar spectrum: treatment implications. Psychopharmacol Bull 23:68–73PubMedGoogle Scholar
  7. 7.
    Akiskal HS, Mendlowicz MV, Jean-Louis G, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL (2005) TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord 85:45–52PubMedCrossRefGoogle Scholar
  8. 8.
    Balazs J, Bitter I, Hideg K, Vitrai J (1998) A MINI és a MINI Plusz kérdõív magyar nyelvû változatának kidolgozása. (Development of the Hungarian version of the MINI. and MINI Plus questionnaires). Psychiatr Hung 13:160–168Google Scholar
  9. 9.
    Beck AT, Weissmann A, Lester D, Trexler L (1974) The measurement of pessimism: the hopelessness scale. J Consult Clin Psychol 42:861–865PubMedCrossRefGoogle Scholar
  10. 10.
    Beitchman JH, Baldassarra L, Mik H, De Luca V, King N, Bender D, Ehtesham S, Kennedy JL (2006) Serotonin transporter polymorphisms and persistent, pervasive childhood aggression. Am J Psychiatry 163:1103–1105PubMedCrossRefGoogle Scholar
  11. 11.
    Bellivier F, Henry C, Szoke A, Schurhoff F, Nosten-Bertrand M, Feingold J, Launay JM, Leboyer M, Laplanche JL (1998) Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci Lett 255:143–146PubMedCrossRefGoogle Scholar
  12. 12.
    Bellivier F, Leroux M, Henry C, Rayah F, Rouillon F, Laplanche JL, Leboyer M (2002) Serotonin transporter gene polymorphism influences age at onset in patients with bipolar affective disorder. Neurosci Lett 334:17–20PubMedCrossRefGoogle Scholar
  13. 13.
    Bengel D, Greenberg BD, Cora-Locatelli G, Altemus M, Heils A, Li Q, Murphy DL (1999) Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol Psychiatry 4:463–466PubMedCrossRefGoogle Scholar
  14. 14.
    Brieger P, Roettig S, Ehrt U, Wenzel A, Bloink R, Marneros A (2003) TEMPS-a scale in ‘mixed’ and ‘pure’ manic episodes: new data and methodological considerations on the relevance of joint anxious-depressive temperament traits. J Affect Disord 73:99–104PubMedCrossRefGoogle Scholar
  15. 15.
    Buss AK (1961) The psychology of aggression. Wiley, New YorkCrossRefGoogle Scholar
  16. 16.
    Cartwright DS (1974) Introduction to personality. Rand McNally, ChicagoGoogle Scholar
  17. 17.
    Cloninger CR, Przybeck TR, Svrakic DM, Wetzel RD (1994) The temperament and character inventory (TCI): a guide to its development and use. Center for psychobiology of personality. Washington University, St. LouisGoogle Scholar
  18. 18.
    Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460PubMedGoogle Scholar
  19. 19.
    Costa PT Jr, McCrae RR (2005) Approaches derived from psychology and psychology. In: Sadock BJ, Sadock VA (eds) Kaplan and Sadock’s comprehensive textbook of psychiatry. Lippincott Williams and Wilkins, Philadelphia, pp 778–794Google Scholar
  20. 20.
    Derogatis LR, Lipman RS, Covi L (1970) Dimensions of outpatient neurotic pathology: comparison of a clinical vs. an empirical assessment. J Consult Clin Psychol 34:164–167PubMedCrossRefGoogle Scholar
  21. 21.
    Du L, Bakish D, Hrdina PD (2000) Gender differences in association between serotonin transporter gene polymorphism and personality traits. Psychiatr Genet 10:159–164PubMedCrossRefGoogle Scholar
  22. 22.
    Ebstein RP (2006) The molecular genetic architecture of human personality: beyond self-report questionnaires. Mol Psychiatry 11:427–445PubMedCrossRefGoogle Scholar
  23. 23.
    Eysenck HJ, Eysenck SBG, Barrett P (1985) A revised version of the psychoticism scale. Pers Individ Diff 6:21–29CrossRefGoogle Scholar
  24. 24.
    Eysenk HJ (1987) The definition of personality disorders and the criteria appropriate for their description. J Personal Disord 1:211–219Google Scholar
  25. 25.
    Gonda X, Juhasz G, Laszik A, Rihmer Z, Bagdy G (2005) Subthreshold depression is linked to the functional polymorphism of the 5HT transporter gene. J Affect Disord 87:291–297PubMedCrossRefGoogle Scholar
  26. 26.
    Gonda X, Rihmer Z, Juhasz G, Zsombok T, Bagdy G (2007) High anxiety and migraine are associated with the s allele of the 5HTTLPR gene polymorphism. Psychiatry Res 149:261–266PubMedCrossRefGoogle Scholar
  27. 27.
    Gonda X, Rihmer Z, Zsombok T, Bagdy G, Akiskal KK, Akiskal HS (2006) The 5HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A. J Affect Disord 91:125–131PubMedCrossRefGoogle Scholar
  28. 28.
    Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87PubMedCrossRefGoogle Scholar
  29. 29.
    Hajnal A, Varady G, Vaczi P (1982) Szubjektív tünetlista (SCL-51) alkalmazásánál nyert tapasztalatok neurotikus betegeknél. Ideggyógyászati Szemle 35:272–275Google Scholar
  30. 30.
    Hantouche EG, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM, Bourgeois M, Fraud JP, Chatenet-Duchene L (1998) Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 50:163–173PubMedCrossRefGoogle Scholar
  31. 31.
    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624PubMedCrossRefGoogle Scholar
  32. 32.
    John OP, Donahue BM, Kentle RL (1991) The big five inventory: versions 4a and 54. Technical report. University of California, Institute of Personality and Social Research, BerkeleyGoogle Scholar
  33. 33.
    Katsuragi S, Kunugi H, Sano A, Tsutsumi T, Isogawa K, Nanko S, Akiyoshi J (1999) Association between serotonin transporter gene polymorphism and anxiety-related traits. Biol Psychiatry 45:368–370PubMedCrossRefGoogle Scholar
  34. 34.
    Kendler KS, Gardner CO Jr (1998) Boundaries of major depression: an evaluation of DSM-IV criteria. Am J Psychiatry 155:172–177PubMedGoogle Scholar
  35. 35.
    Kendler KS, Gatz M, Gardner CO, Pedersen NL (2006) Personality and major depression: a Swedish longitudinal, population-based twin study. Arch Gen Psychiatry 63:1113–1120PubMedCrossRefGoogle Scholar
  36. 36.
    Kesebir S, Vahip S, Akdeniz F, Yuncu Z, Alkan M, Akiskal H (2005) Affective temperaments as measured by TEMPS-A in patients with bipolar I disorder and their first-degree relatives: a controlled study. J Affect Disord 85:127–133PubMedCrossRefGoogle Scholar
  37. 37.
    Khan AA, Jacobson KC, Gardner CO, Prescott CA, Kendler KS (2005) Personality and comorbidity of common psychiatric disorders. Br J Psychiatry 186:190–196PubMedCrossRefGoogle Scholar
  38. 38.
    Lee R, Coccaro E (2001) The neuropsychopharmacology of criminality and aggression. Can J Psychiatry 46:35–44PubMedGoogle Scholar
  39. 39.
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  40. 40.
    Matolcsi A (1984) Az Eysenck-féle személyiség-kérdőív magyar változata; a magyar és az angol felnőttek összehasonlító vizsgálata. Pszichológia 4:231–240Google Scholar
  41. 41.
    Matthews G, Deary IJ (1998) Personality traits. Cambrdige University Press, CambridgeGoogle Scholar
  42. 42.
    Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M, Linnoila M, Goldman D (1998) Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry 55:936–940PubMedCrossRefGoogle Scholar
  43. 43.
    McCrae RR, Costa PT Jr (1996) Toward a new generation of personality theories: theoretical contexts for the five-factor model. In: Wiggins JS (ed) The five-factor model of personality: theoretical perspectives. Guilford, New York, pp 51–87Google Scholar
  44. 44.
    McMillan D, Gilbody S, Beresford E, Neilly L (2007) Can we predict suicide and non-fatal self-harm with the beck hopelessness scale? A meta-analysis. Psychol Med 37:769–778PubMedCrossRefGoogle Scholar
  45. 45.
    Melke J, Landen M, Baghei F, Rosmond R, Holm G, Bjorntorp P, Westberg L, Hellstrand M, Eriksson E (2001) Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women. Am J Med Genet 105:458–463PubMedCrossRefGoogle Scholar
  46. 46.
    Miller JD, Pilkonis PA (2006) Neuroticism and affective instability: the same or different? Am J Psychiatry 163:839–845PubMedCrossRefGoogle Scholar
  47. 47.
    Munnich I (1998) A Buss–Durkee féle agressziót mérő kérdőív. In: Merei F, Szakacs F (eds) Pszichodiagnosztikai Vademecum. Nemzeti Tankönyvkiadó, Budapest, pp 174–192Google Scholar
  48. 48.
    Perczel-Forintos D, Sallai J, Rozsa S (2001) A Beck-féle reménytelenség skála pszichometriai vizsgálata. Psychiatr Hung 16:632–643Google Scholar
  49. 49.
    Rozsa S, Kallai J, Osvath A, Banki MC (2005) Temperamentum és Karakter: Cloninger pszichobiológiai modellje. A Cloninger-féle Temperamentum és Karakter Kérdőív felhasználói kézikönyve. Medicina, BudapestGoogle Scholar
  50. 50.
    Rozsa S, Rihmer A, Ko N, Gonda X, Szili I, Szadoczky E, Pestality P, Rihmer Z (2006) Az affektív temperamentum: a TEMPS-A kérdőívvel serzett hazai tapasztalatok. Psychiatr Hung 21:147–160PubMedGoogle Scholar
  51. 51.
    Rozsa S, Rihmer Z, Gonda X, Szili I, Rihmer A, Ko N, Nemeth A, Pestality P, Bagdy G, Alhasoon O, Akiskal K, Akiskal HS (2008) A study of affective temperaments in Hungary: internal consistency and concurrent validity of the TEMPS-A against the TCI and NEO PI-R. J Affect Disord (in press)Google Scholar
  52. 52.
    Sen S, Burmeister M, Ghosh D (2004) Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet 127:85–89CrossRefGoogle Scholar
  53. 53.
    Sheehan D, Lecrubier Y (1997) Reliability and validity of the MINI international neuropsychiatric interview (MINI) according to the SCID-P. Eur J Psychiatry 12:232–241CrossRefGoogle Scholar
  54. 54.
    Simon A (1998) A Zung-féle depresszió-skála (The Zung self-rating depression scale). In: Merei F, Szakacs F (eds) Pszichodiagnosztikai Vademecum. Nemzeti Tankönyvkiadó, Budapest, pp 180–185Google Scholar
  55. 55.
    Sipos K, Sipos M, Spielberger CD (1998) A state-trait anxiety inventory (STAI) magyar változata. In: Merei F, Szakacs F (eds) Pszichodiagnosztikai Vademecum I. Explorációs és biográfiai módszerek, tünetbecslő skálák, kérdőívek, 2. rész. Nemzeti Tankönyvkiadó, Budapest, pp 123–136Google Scholar
  56. 56.
    Spielberger CD (1970) Manual for the state-trait anxiety inventory. Consulting Psychologists Press, Palo AltoGoogle Scholar
  57. 57.
    Walsh PS, Metzger DA, Higuchi R (1991) Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 10:506–513PubMedGoogle Scholar
  58. 58.
    Wasserman D, Geijer T, Sokolowski M, Frisch A, Michaelovsky E, Weizman A, Rozanov V, Wasserman J (2007) Association of the serotonin transporter promotor polymorphism with suicide attempters with a high medical damage. Eur Neuropsychopharmacol 17:230–233PubMedCrossRefGoogle Scholar
  59. 59.
    Zung WWK (1965) A self-rating depression scale. Arch Gen Psychiatry 12:63–70PubMedGoogle Scholar

Copyright information

© Steinkopff Verlag Darmstadt 2008

Authors and Affiliations

  • Xenia Gonda
    • 1
    • 2
    Email author
  • Konstantinos N. Fountoulakis
    • 3
  • Gabriella Juhasz
    • 4
  • Zoltan Rihmer
    • 1
  • Judit Lazary
    • 2
  • Andras Laszik
    • 5
  • Hagop S. Akiskal
    • 6
    • 7
    • 8
  • Gyorgy Bagdy
    • 2
    • 9
  1. 1.Dept. of Clinical and Theoretical Mental Health, Kutvolgyi Clinical CentreSemmelweis UniversityBudapestHungary
  2. 2.Dept. of Pharmacology and PharmacotherapySemmelweis UniversityBudapestHungary
  3. 3.3rd Dept. of PsychiatryAristotle University, University Hospital AHEPAThessalonikiGreece
  4. 4.Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human SciencesThe University of ManchesterManchesterUK
  5. 5.Institute of Forensic MedicineSemmelweis UniversityBudapestHungary
  6. 6.International Mood CenterLa JollaUSA
  7. 7.Union of Depressive and Manic-depressive AssociationRennesFrance
  8. 8.Dept. of PsychiatryUniversity of California at San DiegoLa JollaUSA
  9. 9.Group of Neuropsychopharmacology, Hungarian Academy of SciencesSemmelweis UniversityBudapestHungary

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