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Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis
Open accessAbstract
CONTEXT: Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE: To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES: Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION: Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION: Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS: In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION: This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
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“a recent meta-analysis by Risch et al. (2009) examined GxE between stressful life events and 5-HTTLPR on depression using 14 studies (N=14,250). Just under half of the included studies focused on the effects of ELS. The authors concluded that there was no support for an interaction effect”
From Gene–environment interactions: early life stress and risk for depressive and anxiety disorders (2011) · cites this paper as Risch et al. (2009)
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“This association did not replicate in an independent but similar study from the same geographic region, casting particular doubt on the reported association. 115”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [115]
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BackgroundInfluentialSelf-citationVeletza, S. V., Samakouri, M. A., Emmanouil, G., Trypsianis, G., Kourmouli, N., & Livaditis, M. (2008) · Synapse · doi:10.1002/syn.20598 · Cited by 19
Katsuyama, H., Tomita, M., Hidaka, K., Fushimi, S., Okuyama, T., WATANABE, Y., Tamechika, Y., Otsuki, T., Saijoh, K., & Sunami, S. (2008) · International Journal of Molecular Medicine · doi:10.3892/ijmm.21.4.499 · Cited by 11 · cited 4×
“Middeldorp et al,29 2008 1154 (785) 39 (26-65) 33 49 19 Prospective cohort Twins Studyspecific AnxietyDepression Rating Scale Failed to replicate”
BackgroundInfluentialBegley, S. (2008) · PubMed · Cited by 5
Serotonin Transporter, Stressful Life Events, and Depression Severity
Joober, R., Sengupta, S. M., & Schmitz, N. (2007) · American Journal of Psychiatry · doi:10.1176/ajp.2007.164.5.829b · Cited by 3 · cited 6×
“Wilhelm et al,27 2006 127 (85) 48 (44-52) 30 49 21 Prospective cohort No List of Threatening Eventsb Major depression (DSM-IV) Replication”
BackgroundInfluential
Flagged first, then by citations
1 of the 69 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- [14]Gene X environment interactions and developmental psychopathology National Institute of Mental Health Workshop Research Challenges and Opportunities June 27 28 2006 Washington, DC
- [61]Breakthrough of the year: the runners-up Science 2003 302 5653 2039 2045 14700029
Cited by
Sorted by citations
Beyond diathesis stress: differential susceptibility to environmental influences
Belsky, J., & Pluess, M. (2009) · Psychological Bulletin · doi:10.1037/a0017376 · Cited by 3,039
Cognition and Depression: Current Status and Future Directions
Gotlib, I. H., & Joormann, J. (2010) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.121208.131305 · Cited by 2,420
Thapar, A., Collishaw, S., Pine, D. S., & Thapar, A. K. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60871-4 · Cited by 2,365
Otte, C., Gold, S. M., Penninx, B. W., Pariante, C. M., Etkin, A., Fava, M., Mohr, D. C., & Schatzberg, A. F. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.65 · Cited by 2,269
Belmaker, R. H., & Agam, G. (2008) · New England Journal of Medicine · doi:10.1056/nejmra073096 · Cited by 2,166
Metadata
- Authors
- Risch, N., Herrell, R., Lehner, T., Liang, K.-Y., Eaves, L., Hoh, J., Griem, A., Kovacs, M., Ott, J., & Merikangas, K. R.
- Affiliations
- University of California, San Francisco (US)
- National Institutes of Health (US)
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2009-06-17
- Volume
- 301
- Issue
- 23
- Pages
- 2462
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC2938776
- OpenAlex
- W2042170262
- Cited by
- 1,655
- References
- 69
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 12 · 2023: 33 · 2022: 21 · 2021: 49 · 2020: 68 · 2019: 64 · 2018: 70 · 2017: 89 · 2016: 114 · 2015: 138 · 2014: 130 · 2013: 147 · 2012: 176
- FWCI
- 94.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Institute of Mental Health (Z01MH002804)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- 5-HTTLPR, serotonin transporter gene, life events, major depressive disorder, gene-environment interaction, short allele, depression risk, sex differences, genetic susceptibility, microdata
- MeSH terms
- Depressive Disorder, Major, Major Depressive Disorder, Female, Genotype, Humans, Life Change Events, Male, Risk Factors, Stress, Psychological, Serotonin Plasma Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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