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The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort

Abstract

We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X2=4.7, P=0.09 (crude), LR-X2=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X2=6.9, P=0.032 (crude), LR-X2=8.1, P=0.017 (adjusted)).

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References

  1. Bebbington PE, Brugha T, MacCarthy B, Potter J, Sturt E, Wykes T et al. The Camberwell Collaborative Depression Study. I. Depressed probands: adversity and the form of depression. Br J Psychiatry 1988; 152: 754–765.

    Article  CAS  Google Scholar 

  2. Brown GW, Andrews B, Harris T, Adler Z, Bridge L . Social support, self-esteem and depression. Psychol Med 1986; 16: 813–831.

    Article  CAS  Google Scholar 

  3. Cervilla JA, Prince MJ . Cognitive impairment and social distress as different pathways to depression in the elderly: a cross-sectional study. Int J Geriatr Psychiatry 1997; 12: 995–1000.

    Article  CAS  Google Scholar 

  4. Farmer A, Harris T, Redman K, Sadler S, Mahmood A, McGuffin P . Cardiff depression study. A sib-pair study of life events and familiality in major depression. Br J Psychiatry 2000; 176: 150–155.

    Article  CAS  Google Scholar 

  5. 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: 1527–1531.

    Article  CAS  Google Scholar 

  6. Furlong RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES et al. Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am J Med Genet 1998; 81: 58–63.

    Article  CAS  Google Scholar 

  7. Gutierrez B, Pintor L, Gasto C, Rosa A, Bertranpetit J, Vieta E et al. Variability in the serotonin transporter gene and increased risk for major depression with melancholia. Hum Genet 1998; 103: 319–322.

    Article  CAS  Google Scholar 

  8. Lotrich FE, Pollock BG . Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet 2004; 14: 121–129.

    Article  Google Scholar 

  9. Cervilla JA, Rivera M, Molina E, Torres-Gonzalez F, Bellón J, Moreno B et al. The 5HTTLPR genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: The PREDICT-Gene Study. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 912–917.

    Article  CAS  Google Scholar 

  10. Collier DA, Stober G, Li T, Heils A, Catalano M, DiBella D et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: Possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1: 453–460.

    CAS  Google Scholar 

  11. Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8: 574–591.

    Article  CAS  Google Scholar 

  12. 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: 386–389.

    Article  CAS  Google Scholar 

  13. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT . Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B-Neuropsychiatr Genet 2005; 133B: 110–115.

    Article  Google Scholar 

  14. Garrod AE . The incidence of alkaptonuria: a study in chemical individuality. 1902 [classical article]. Yale J Biol Med 2002; 75: 221–231.

    PubMed  PubMed Central  Google Scholar 

  15. Hunter DJ . Gene–environment interactions in human diseases. Nat Rev Genet 2005; 6: 287–298.

    Article  CAS  Google Scholar 

  16. Barr CS, Newman TK, Shannon C, Parker C, Dvoskin RL, Becker ML et al. Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry 2004; 55: 733–738.

    Article  CAS  Google Scholar 

  17. 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: 400–403.

    Article  CAS  Google Scholar 

  18. Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P et al. Gene–environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 2004; 9: 908–915.

    Article  CAS  Google Scholar 

  19. Grabe HJ, Lange M, Wolff B, Volzke H, Lucht M, Freyberger HJ et al. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry 2005; 10: 220–224.

    Article  CAS  Google Scholar 

  20. Kaufman J, Yang BZ, Douglas-Palumberi H, Houshyar S, Lipschitz D, Krystal JH et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci USA 2004; 101: 17316–17321.

    Article  CAS  Google Scholar 

  21. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B . The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005; 62: 529–535.

    Article  CAS  Google Scholar 

  22. Sjoberg RL, Nilsson KW, Nordquist N, Ohrvik J, Leppert J, Lindstrom L et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006; 9: 1–7.

    Article  Google Scholar 

  23. Wilhelm K, Mitchell PB, Niven H, Finch A, Wedgwood L, Scimone A et al. Life events, first depression onset and the serotonin transporter gene. Br J Psychiatry 2006; 188: 210–215.

    Article  Google Scholar 

  24. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG . The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol Med 2005; 35: 101–111.

    Article  Google Scholar 

  25. Surtees PG, Wainwright NW, Willis-Owen SA, Luben R, Day NE, Flint J . Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biol Psychiatry 2006; 59: 224–229.

    Article  CAS  Google Scholar 

  26. Zammit S, Owen MJ . Stressful life events, 5-HTT genotype and risk of depression. Br J Psychiatry 2006; 188: 199–201.

    Article  Google Scholar 

  27. King M, Weich S, Torres F, Svab I, Maaroos H, Neeleman J et al. Prediction of depression in European general practice attendees: the PREDICT study. BMC Public Health 2006; 6: 6.

    Article  Google Scholar 

  28. Brugha TS, Cragg D . The List of Threatening Experiences: the reliability and validity of a brief life events questionnaire. Acta Psychiatr Scand 1990; 82: 77–81.

    Article  CAS  Google Scholar 

  29. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J et al. The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 1988; 45: 1069–1077.

    Article  CAS  Google Scholar 

  30. World Health Organisation. ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research, 1st edn. World Health Organisation: Geneva, 1993.

  31. STATA Statistical Software. Release 9. Stata Corporation: College Station, TX, 2006.

  32. Hu XZ, Lipsky RH, Zhu GS, Akhtar LA, Taubman J, Greenberg BD et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78: 815–826.

    Article  CAS  Google Scholar 

  33. Parsey RV, Hastings RS, Oquendo MA, Hu XZ, Goldman D, Huang YY et al. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 2006; 163: 48–51.

    Article  Google Scholar 

  34. Mandelli L, Serretti A, Marino E, Pirovano A, Calati R, Colombo C . Interaction between serotonin transporter gene, catechol-O-methyltransferase gene and stressful life events in mood disorders. Int J Neuropsychopharmacol 2006; 7: 1–11.

    Google Scholar 

  35. Caspi A, Moffitt TE, Thornton A, Freedman D, Amell JW, Harrington H et al. The life history calendar: A research and clinical assessment method for collecting retrospective event-history data. Int J Methods Psychiatr Res 1996; 6: 101–114.

    Article  Google Scholar 

  36. Jones I . Genetics of Affective Disorder. In: McGuffin P (ed). Psychiatr Genet Genomics. Cambridge University Press: London, 2004, pp 223–224.

    Google Scholar 

  37. McGuffin P, Katz R, Bebbington P . The Camberwell Collaborative Depression Study. 3. Depression and Adversity in the Relatives of Depressed Probands. Br J Psychiatr 1988; 152: 775–782.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the PREDICT study Core Group members (Miguel Xavier, Igor Slav, Heidi-Ingrid Maaros, Jan Neelman, Francisco Torres-González, Irwing Nazareth and Michael King) for agreeing to include a genetic sub-study to their ongoing study. We also thank the three interviewers (Francisca Vidal, Nuria López and Ana Álvarez) and all nurses and general practitioners at all nine primary care centres in Málaga (Spain) for their collaboration and hard work in collecting most of the data. This study was co-funded by the fifth Framework Program of the European Commission, a grant from the Ministry of Education and Science (SAF-2004-01310) and by I+D+I Grant from the Ministry of Education and Science SAF2006-07192.

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Cervilla, J., Molina, E., Rivera, M. et al. The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort. Mol Psychiatry 12, 748–755 (2007). https://doi.org/10.1038/sj.mp.4001981

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