The DOI matches its Crossref record; 68 of the 69 references it cites were found in a registry or an index.
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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Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
The Future of Genetic Studies of Complex Human Diseases
Risch, N., & Merikangas, K. (1996) · Science · doi:10.1126/science.273.5281.1516 · Cited by 5,355 · cited 1×
“Strengths of the analysis reported herein include: (1) use of the same variable definitions (ie, the number of S alleles and an ordinal measure of life events) and analytic approach that was used in the original report in order to provide a valid test of replication; (2) inclusion of primary data from numerous studies…”
MethodSelf-citationRole of genotype in the cycle of violence in maltreated children
Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., Taylor, A., & Poulton, R. (2002) · Science · doi:10.1126/science.1072290 · Cited by 4,842 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialDean, M. C., Carrington, M. N., Winkler, C. A., Huttley, G. A., Smith, M. W., Allikmets, R. L., Goedert, J. J., Buchbinder, S., Vittinghoff, E., Gomperts, E. D., et al. (1996) · Science · doi:10.1126/science.273.5283.1856 · Cited by 2,503 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialLohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., & Hirschhorn, J. N. (2003) · Nature Genetics · doi:10.1038/ng1071 · Cited by 1,900
Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., et al. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.026 · Cited by 1,409 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialReplicating genotype–phenotype associations
NCI-NHGRI Working Group on Replication in Association Studies, Chanock, S. J., Manolio, T., Boehnke, M., Boerwinkle, E., Hunter, D. J., Thomas, G., Hirschhorn, J. N., Abecasis, G., Altshuler, D., et al. (2007) · Nature · doi:10.1038/447655a · Cited by 1,352
Self-citationGene–environment interactions in human diseases
Hunter, D. J. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1578 · Cited by 1,132 · cited 2×
“Strengths of the analysis reported herein include: (1) use of the same variable definitions (ie, the number of S alleles and an ordinal measure of life events) and analytic approach that was used in the original report in order to provide a valid test of replication; (2) inclusion of primary data from numerous studies…”
MethodBrugha, T. S., Bebbington, P., Tennant, C., & Hurry, J. (1985) · Psychological Medicine · doi:10.1017/s003329170002105x · Cited by 1,108 · cited 5×
“Surtees et al,25 2006 4175 (1950) 60 (41-80) 33 49 18 Crosssectional No List of Threatening Eventsb Major depression (DSM-IV) Failed to replicate”
BackgroundInfluentialAllen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P. A., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., & Bertram, L. (2008) · Nature Genetics · doi:10.1038/ng.171 · Cited by 1,054
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
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Wells, J. L., Brown, C. L., Hua, A. Y., Soyster, P. D., Chen, K., Dokuru, D. R., Coppola, G., Haase, C. M., & LEVENSON, R. W. (2019) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2019.04.009 · Cited by 15
Latendresse, S. J., Musci, R., & Maher, B. S. (2018) · Prevention Science · doi:10.1007/s11121-017-0785-1 · Cited by 12
“…available data reached conflicting conclusions regarding the mediation of the relationship between stress and depression by 5-HTTLPR, a finding (Caspi et al. 2003) that received unparalleled attention and nearly fostered a subfield aimed at its replication (Munafò et al. 2009; Risch et al. 2009).”
Parenting Interacts With Plasticity Genes in Predicting Behavioral Outcomes in Preschoolers
Letourneau, N. L., de Koning, A. P. J., Sekhon, B., Ntanda, H. N., Kobor, M., Deane, A. J., Morin, A. M., Dewey, D., Campbell, T. S., Giesbrecht, G. F., et al. (2020) · Canadian Journal of Nursing Research · doi:10.1177/0844562119863612 · Cited by 12
“To our knowledge, while many studies have examined interactions between stressful life events including parental maltreatment and 5-HTTLPR in predicting mental health (Karg et al., 2011; Munafò, Durrant, Lewis, & Flint, 2009; Risch et al., 2009), the degree to which aspects of parent–child relationship quality (such a…”
BackgroundResultInfluentialAcosta, H., Kantojärvi, K., Tuulari, J. J., Lewis, J. D., Hashempour, N., Scheinin, N. M., Lehtola, S. J., Nolvi, S., Fonov, V. S., Collins, D. L., et al. (2024) · Development and Psychopathology · doi:10.1017/s0954579423000275 · Cited by 11
“Of note, weaker transcriptional activity of SLC6A4 has originally been considered as conferring sensitivity to environmental influences, but this view has been challenged by large meta-analyses (Culverhouse et al., 2018; Heils et al., 1996; Risch et al., 2009).”
InfluentialSteffen, P. R., Austin, T., & DeBarros, A. (2017) · Policy Insights from the Behavioral and Brain Sciences · doi:10.1177/2372732216685333 · Cited by 15
“Many studies have since addressed this topic, but several meta-analyses have failed to establish the gene-by-environment interaction between stress and the short allele (Munafò, Durrant, Lewis, & Flint, 2009; Risch et al., 2009).”
BackgroundSaul, A., Taylor, B., Simpson, S., Ponsonby, A.-L., Blizzard, L., Dwyer, T., McMorran, B., Wood, B., & van der Mei, I. A. (2019) · Multiple Sclerosis Journal · doi:10.1177/1352458518770021 · Cited by 9
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
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