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Gene–environment interactions predict cortisol responses after acute stress: Implications for the etiology of depression
Abstract
Background Growing evidence suggests that the serotonin transporter polymorphism (5-HTTLPR) interacts with adverse environmental influences to produce an increased risk for the development of depression while the underlying mechanisms of this association remain largely unexplored. As one potential intermediate phenotype, we investigated alterations of hypothalamic-pituitary-adrenal (HPA) axis responses to stress in individuals with no history of psychopathology depending on both 5-HTTLPR and stressful life events.Methods Healthy male adults (N=100) were genotyped and completed a questionnaire on severe stressful life events (Life Events Checklist). To test for gene-by-environment interactions on endocrine stress reactivity, subjects were exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol levels were obtained at 6 time points prior to the stressor and during an extended recovery period.Results Subjects homozygous for the s-allele with a significant history of stressful life events exhibited markedly elevated cortisol secretions in response to the stressor compared to all other groups, indicating a significant gene-by-environment interaction on endocrine stress reactivity. No main effect of either 5-HTTLPR (biallelic and triallelic) or stressful life events on cortisol secretion patterns appeared.Conclusion This is the first study reporting that 5-HTTLPR and stressful life events interact to predict endocrine stress reactivity in a non-clinical sample. Our results underpin the potential moderating role of HPA-axis hyper-reactivity as a premorbid risk factor to increase the vulnerability for depression in subjects with low serotonin transporter efficiency and a history of severe life events.
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“Consistent with this, the s′ allele of 5-HTTLPR has been associated with an exaggerated cortisol response to a standardized psychosocial stressor in children and adults (Alexander et al. 2009; Gotlib et al. 2008).”
From Gene–environment interactions: early life stress and risk for depressive and anxiety disorders (2011) · cites this paper as Alexander et al. 2009
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Kostic, M. V., Canu, E., Agosta, F., Munjiza, A., Novaković, I. V., Dobričić, V., Ferraro, P. M., Miler-Jerković, V., Pekmezovic, T. D., Toševski, D. L., et al. (2016) · Human Brain Mapping · doi:10.1002/hbm.23165 · Cited by 16
Wassink, L., Bussy, U., Li, W., & Scribner, K. T. (2019) · Animal Behaviour · doi:10.1016/j.anbehav.2019.09.005 · Cited by 16
Zeev‐Wolf, M., Lévy, J., Ebstein, R. P., & Feldman, R. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00335 · Cited by 16
Metadata
- Authors
- Alexander, N., Kuepper, Y., Schmitz, A., Osinsky, R., Kozyra, E., & Hennig, J.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- Corresponding author
- Alexander, Nina
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 34
- Issue
- 9
- Pages
- 1294-1303
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2043334194
- Cited by
- 171
- References
- 90
- Citations by year
- 2026: 1 · 2025: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 13 · 2017: 10 · 2016: 11 · 2015: 14 · 2014: 19 · 2013: 13 · 2012: 26
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- gene-environment interaction, 5-HTTLPR, serotonin transporter polymorphism, cortisol, acute stress, life events, depression risk, salivary cortisol, premorbid risk factors
- MeSH terms
- Adult, Depression, Genotype, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Life Change Events, Male, Pituitary-Adrenal System, Saliva, Speech, Stress, Psychological, Serotonin Plasma Membrane Transport Proteins
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