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Science 301 (5631): 386-389

Copyright © 2003 by the American Association for the Advancement of Science

Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

Avshalom Caspi,1,2 Karen Sugden,1 Terrie E. Moffitt,1,2* Alan Taylor,1 Ian W. Craig,1 HonaLee Harrington,2 Joseph McClay,1 Jonathan Mill,1 Judy Martin,3 Antony Braithwaite,4 Richie Poulton3

Abstract: In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.

1 Medical Research Council Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, PO80 De Crespigny Park, London, SE5 8AF, UK. 2 Department of Psychology, University of Wisconsin, Madison, WI 53706, USA. 3 Dunedin School of Medicine, 4 Department of Pathology, University of Otago, Dunedin, New Zealand.

* To whom correspondence should be addressed. E-mail: t.moffitt{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
Ambulatory Monitoring in the Genetics of Psychosomatic Medicine.
P. H. Finan, H. Tennen, F. Thoemmes, A. J. Zautra, and M. C. Davis (2012)
Psychosom Med 74, 349-355
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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E. Palazidou (2012)
Br. Med. Bull. 101, 127-145
   Abstract »    Full Text »    PDF »
Vesicular and Plasma Membrane Transporters for Neurotransmitters.
R. D. Blakely and R. H. Edwards (2012)
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   Abstract »    Full Text »    PDF »
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C. R. Quinn, C. Dobson-Stone, T. Outhred, A. Harris, and A. H. Kemp (2012)
Australian and New Zealand Journal of Psychiatry 46, 55-63
   Abstract »    Full Text »    PDF »
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R. L. Simons, M. K. Lei, E. A. Stewart, S. R. H. Beach, G. H. Brody, R. A. Philibert, and F. X. Gibbons (2012)
Youth Violence and Juvenile Justice 10, 3-24
   Abstract »    PDF »
The Interaction Between Neighborhood Disadvantage and Genetic Factors in the Prediction of Antisocial Outcomes.
K. M. Beaver, C. L. Gibson, M. DeLisi, M. G. Vaughn, and J. P. Wright (2012)
Youth Violence and Juvenile Justice 10, 25-40
   Abstract »    PDF »
Impact of institutional care on attachment disorganization and insecurity of Ukrainian preschoolers: Protective effect of the long variant of the serotonin transporter gene (5HTT).
M. J. Bakermans-Kranenburg, N. Dobrova-Krol, and M. van IJzendoorn (2012)
International Journal of Behavioral Development 36, 11-18
   Abstract »    PDF »
Cortisol response to behavior problems in FMR1 premutation mothers of adolescents and adults with fragile X syndrome: A diathesis-stress model.
S. L. Hartley, M. M. Seltzer, J. Hong, J. S. Greenberg, L. Smith, D. Almeida, C. Coe, and L. Abbeduto (2012)
International Journal of Behavioral Development 36, 53-61
   Abstract »    PDF »
Serotonin Transporter Gene Polymorphism, Childhood Trauma, and Cognition in Patients With Psychotic Disorders.
M. Aas, S. Djurovic, L. Athanasiu, N. E. Steen, I. Agartz, S. Lorentzen, K. Sundet, O. A. Andreassen, and I. Melle (2012)
Schizophr Bull 38, 15-22
   Abstract »    Full Text »    PDF »
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J.-M. Kim, S.-W. Kim, R. Stewart, S.-Y. Kim, I.-S. Shin, M.-H. Park, J.-H. Yoon, J.-S. Lee, S.-W. Park, Y.-H. Kim, et al. (2012)
Psychosom Med 74, 8-15
   Abstract »    Full Text »    PDF »

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