Skip to main content Accessibility help

Mechanisms of gene–environment interactions in depression: evidence that genes potentiate multiple sources of adversity

  • M. Wichers (a1), D. Schrijvers (a2), N. Geschwind (a1), N. Jacobs (a1) (a3), I. Myin-Germeys (a1), E. Thiery (a4), C. Derom (a5), B. Sabbe (a2), F. Peeters (a1), Ph. Delespaul (a1) and J. van Os (a1) (a6)...



Previous work suggests that daily life stress-sensitivity may be an intermediary phenotype associated with both genetic risk for depression and developmental stress exposures. In the current analysis we hypothesized that genetic risk for depression and three environmental exposures over the course of development [prenatal stress, childhood adversity and adult negative life events (NLEs)] combine synergistically to produce the phenotype of stress-sensitivity.


Twin pairs (n=279) participated in a momentary assessment study using the Experience Sampling Method (ESM), collecting appraisals of stress and negative affect (NA) in the flow of daily life. Prospective data on birthweight and gestational age, questionnaire data on childhood adversity and recent NLEs, and interview data on depression were used in the analyses. Daily life stress-sensitivity was modelled as the effect of ESM daily life stress appraisals on ESM NA.


All three developmental stress exposures were moderated by genetic vulnerability, modelled as dizygotic (DZ) or monozygotic (MZ) co-twin depression status, in their effect on daily life stress-sensitivity. Effects were much stronger in participants with MZ co-twin depression and a little stronger in participants with DZ co-twin depression status, compared to those without co-twin depression. NLE main effects and NLE genetic moderation were reducible to birthweight and childhood adversity.


The findings are consistent with the hypothesis that adult daily life stress-sensitivity is the result of sensitization processes initiated by developmental stress exposures. Genes associated with depression may act by accelerating the process of stress-induced sensitization.


Corresponding author

*Address for correspondence: Dr M. Wichers, Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University Medical Centre, Vijverdalseweg 1, Concorde Building, Maastricht, The Netherlands. (Email:


Hide All
Arntz, A, Wessel, I (1996). Jeugd Trauma Vragenlijst [Dutch version of the Childhood Trauma Questionnaire]. Maastricht.
Bernstein, DP, Ahluvalia, T, Pogge, D, Handelsman, L (1997). Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population. Journal of the American Academy of Child and Adolescent Psychiatry 36, 340348.
Bernstein, DP, Fink, L, Handelsman, L, Foote, J, Lovejoy, M, Wenzel, K, Sapareto, E, Ruggiero, J (1994). Initial reliability and validity of a new retrospective measure of child abuse and neglect. American Journal of Psychiatry 151, 11321136.
Caspi, A, Sugden, K, Moffitt, TE, Taylor, A, Craig, IW, Harrington, H, McClay, J, Mill, J, Martin, J, Braithwaite, A, Poulton, R (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386389.
Cohen, J (1988). Statistical Power Analysis for the Behavioral Sciences. Lawrence Earlbaum Associates: Hillsdale, NJ.
Csikszentmihalyi, M, Larson, R (1987). Validity and reliability of the Experience-Sampling Method. Journal of Nervous and Mental Disease 175, 526536.
Delespaul, P (1995). Assessing Schizophrenia in Daily Life: The Experience Sampling Method. University of Limburg: Maastricht.
Derom, CA, Vlietinck, RF, Thiery, EW, Leroy, FO, Fryns, JP, Derom, RM (2006). The East Flanders Prospective Twin Survey (EFPTS). Twin Research and Human Genetics 9, 733738.
DeVries, MW (ed.) (1992). The Experience of Psychopathology: Investigating Mental Disorders in their Natural Settings. Cambridge University Press: Cambridge.
Friis, RH, Wittchen, HU, Pfister, H, Lieb, R (2002). Life events and changes in the course of depression in young adults. European Psychiatry 17, 241253.
Gale, CR, Martyn, CN (2004). Birth weight and later risk of depression in a national birth cohort. British Journal of Psychiatry 184, 2833.
Glaser, JP, van Os, J, Portegijs, PJ, Myin-Germeys, I (2006). Childhood trauma and emotional reactivity to daily life stress in adult frequent attenders of general practitioners. Journal of Psychosomatic Research 61, 229236.
Jacobs, N, Kenis, G, Peeters, F, Derom, C, Vlietinck, R, van Os, J (2006). Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Archives of General Psychiatry 63, 989996.
Kaufman, J, Yang, BZ, Douglas-Palumberi, H, Grasso, D, Lipschitz, D, Houshyar, S, Krystal, JH, Gelernter, J (2006). Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry 59, 673680.
Kendler, KS, Kessler, RC, Walters, EE, MacLean, C, Neale, MC, Heath, AC, Eaves, LJ (1995). Stressful life events, genetic liability, and onset of an episode of major depression in women. American Journal of Psychiatry 152, 833842.
Kendler, KS, Thornton, LM, Gardner, CO (2001). Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. American Journal of Psychiatry 158, 582586.
Kim-Cohen, J, Caspi, A, Taylor, A, Williams, B, Newcombe, R, Craig, IW, Moffitt, TE (2006). MAOA, maltreatment, and gene–environment interaction predicting children's mental health: new evidence and a meta-analysis. Molecular Psychiatry 11, 903913.
Loos, R, Derom, C, Vlietinck, R, Derom, R (1998). The East Flanders Prospective Twin Survey (Belgium): a population-based register. Twin Research 1, 167175.
Monroe, SM, Harkness, KL (2005). Life stress, the ‘kindling’ hypothesis, and the recurrence of depression: considerations from a life stress perspective. Psychological Review 112, 417445.
Myin-Germeys, I, van Os, J, Schwartz, JE, Stone, AA, Delespaul, PA (2001). Emotional reactivity to daily life stress in psychosis. Archives of General Psychiatry 58, 11371144.
Paykel, ES (1997). The Interview for Recent Life Events. Psychological Medicine 27, 301310.
Phillips, DI, Jones, A (2006). Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? Journal of Physiology 572, 4550.
Pohl, J, Olmstead, MC, Wynne-Edwards, KE, Harkness, K, Menard, JL (2007). Repeated exposure to stress across the childhood-adolescent period alters rats' anxiety- and depression-like behaviors in adulthood: the importance of stressor type and gender. Behavioral Neuroscience 121, 462474.
Post, RM (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. American Journal of Psychiatry 149, 9991010.
Rice, F, Harold, GT, Thapar, A (2006). The effect of birth-weight with genetic susceptibility on depressive symptoms in childhood and adolescence. European Child and Adolescent Psychiatry 15, 383391.
Snijders, T, Bosker, R (1999). Multilevel Analysis: An Introduction to Basis and Advanced Multilevel Modeling. Sage: London.
Thompson, C, Syddall, H, Rodin, I, Osmond, C, Barker, DJ (2001). Birth weight and the risk of depressive disorder in late life. British Journal of Psychiatry 179, 450455.
van Dijken, HH, de Goeij, DC, Sutanto, W, Mos, J, de Kloet, ER, Tilders, FJ (1993). Short inescapable stress produces long-lasting changes in the brain– pituitary–adrenal axis of adult male rats. Neuroendocrinology 58, 5764.
van Dijken, HH, Van der Heyden, JA, Mos, J, Tilders, FJ (1992). Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats. Physiology and Behavior 51, 787794.
van Os, J, Wichers, M, Danckaerts, M, Van Gestel, S, Derom, C, Vlietinck, R (2001). A prospective twin study of birth weight discordance and child problem behavior. Biological Psychiatry 50, 593599.
Van Praag, H, De Kloet, ER, Van Os, J (2004). Life events and depression: is there a causal connection? In Stress, the Brain and Depression (ed. Van Praag, H., De Kloet, E. R. and Van Os, J.), pp. 3851. Cambridge University Press: Cambridge.
Viltart, O, Mairesse, J, Darnaudery, M, Louvart, H, Vanbesien-Mailliot, C, Catalani, A, Maccari, S (2006). Prenatal stress alters Fos protein expression in hippocampus and locus coeruleus stress-related brain structures. Psychoneuroendocrinology 31, 769780.
Weekes, NY, Lewis, RS, Goto, SG, Garrison-Jakel, J, Patel, F, Lupien, S (2008). The effect of an environmental stressor on gender differences on the awakening cortisol response. Psychoneuroendocrinology 33, 766772.
Weil, K, Florenzano, R, Vitriol, V, Cruz, C, Carvajal, C, Fullerton, C, Muniz, C (2004). Child battering and adult psychopathology: an empiric study [in Spanish]. Revista Médica de Chile 132, 14991504.
Welberg, LA, Seckl, JR (2001). Prenatal stress, glucocorticoids and the programming of the brain. Journal of Neuroendocrinology 13, 113128.
Wichers, M, Myin-Germeys, I, Jacobs, N, Peeters, F, Kenis, G, Derom, C, Vlietinck, R, Delespaul, P, Van Os, J (2007). Genetic risk of depression and stress-induced negative affect in daily life. British Journal of Psychiatry 191, 218223.
Wust, S, Entringer, S, Federenko, IS, Schlotz, W, Hellhammer, DH (2005). Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology 30, 591598.



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed