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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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Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
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Depression and Cardiovascular Disorders
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“However, a subsequent meta-analysis concluded there was no evidence that the 5-HTTLPR polymorphism, either alone or in interaction with stressful life events, was associated with an elevated risk of depression (Risch et al. 2009).”
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Yao, B., Cheng, Y., Wang, Z., Li, Y., Chen, L., Huang, L., Zhang, W., Chen, D., Wu, H., Tang, B., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01195-y · Cited by 217
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“Nevertheless, research on candidate genes has led to rather contradictory results: in research on the well-known serotonin transporter gene (5-HTTLPR) even meta-analyses differ in their conclusions, 5,6,34 with concerns about publications bias.”
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Genes, Environments, and Time: The Biology of Adversity and Resilience
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Peripheral Markers of Depression
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“Polymorphism in genes encoding the 5-HT transporter, 5-HT2A receptor, BDNF, TRP hydroxylase, SOD and CAT are candidate genes in the pathology of MDD [168,384,385].”
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“Recently, there have been several published critiques of the genotype–environment interplay methdo-logy 160,161 and it is likely that some of the limitations noted by these investigators apply to studies of addiction.”
BackgroundMendelian Randomization for Strengthening Causal Inference in Observational Studies
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Behavior genetics and postgenomics
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Child Maltreatment and Developmental Psychopathology: A Multilevel Perspective
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“This and other studies have shown that the short “s” allele, which results in lower levels of 5-HTT expression (at least in vitro ) and therefore increased extracellular 5-HT, is associated with a higher risk of depression when combined with stressful life events 21,22 .”
ResultDepression research: where are we now?
Lee, S., Jeong, J., Kwak, Y., & Park, S. K. (2010) · Molecular Brain · doi:10.1186/1756-6606-3-8 · Cited by 187
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“(2003)] demonstrated that many have been fraught with methodological and interpretive flaws, including inconsistencies in the designated ‘‘risk’’ genotype(s) and indices of environmental risk across studies as well as loose standards for replication (Munafo et al. 2009; Risch et al. 2009).”
A Genome-Wide Analysis of Liberal and Conservative Political Attitudes
Hatemi, P., Gillespie, N. A., Eaves, L. J., Maher, B. S., Webb, B. T., Heath, A. C., Medland, S. E., Smyth, D. C., Beeby, H. N., Gordon, S. D., et al. (2011) · The Journal of Politics · doi:10.1017/s0022381610001015 · Cited by 157
Self-citationGenes, economics, and happiness.
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Challenges and opportunities in genome-wide environmental interaction (GWEI) studies
Aschard, H., Lutz, S. M., Maus, B., Duell, E. J., Fingerlin, T. E., Chatterjee, N., Kraft, P. L., & Steen, K. V. (2012) · Human Genetics · doi:10.1007/s00439-012-1192-0 · Cited by 149
“However, only a handful of the large number of reported statistically significant interactions has been replicated, despite well-powered replication efforts for some influential preliminary reports (Cornelis et al. 2011; Dunn et al. 2011; Risch et al. 2009).”
Candidate Genes and Political Behavior
Charney, E., & ENGLISH, W. (2012) · American Political Science Review · doi:10.1017/s0003055411000554 · Cited by 148
“2003) (Chipman et al. 2007; Lewis et al. 2010; Power et al. 2010; Surtees et al. 2006; Risch et al. 2009; Hoehe et al. 1998) (Hayden et al.”
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“Substantial controversy was generated by negative findings from two metaanalyses of a subset of these studies (40, 41).”
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Lavebratt, C., Åberg, E., Sjöholm, L. K., & Forsell, Y. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.02.113 · Cited by 142
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Olsson, C. A., Foley, D. L., Parkinson-Bates, M., Byrnes, G., McKenzie, M., Patton, G. C., Morley, R., Anney, R. J. L., Craig, J. M., & Saffery, R. (2010) · Biological Psychology · doi:10.1016/j.biopsycho.2009.12.003 · Cited by 137
Willcutt, E. G., Pennington, B. F., Duncan, L. E., Smith, S. D., Keenan, J. M., Wadsworth, S. J., DeFries, J. C., & Olson, R. K. (2010) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0b013e3181ef42a1 · Cited by 150
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“Stress is the most common risk factor for the development of mood disorders like MDD that are thought to result from interactions between genetic predispositions and environmental factors (Risch et al., 2009).”
BackgroundNeurobiological correlates of illness progression in the recurrent affective disorders
Post, R. M., Fleming, J., & Kapczinski, F. P. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.02.004 · Cited by 142
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“The first misunderstanding is the assumption that to find a replicable G E interaction, one would need a genetic main effect (e.g., Munafò Zammit, & Flint, in press; Risch et al., 2009).”
BackgroundWeiß, A., Adams, M. J., Widdig, A., & Gerald, M. S. (2011) · Journal of comparative psychology · doi:10.1037/a0021187 · Cited by 138
The Neurobiological Mechanisms of Generalized Anxiety Disorder and Chronic Stress
Patriquin, M. A., & Mathew, S. J. (2017) · Chronic Stress · doi:10.1177/2470547017703993 · Cited by 156
FADS2 Polymorphisms Modify the Effect of Breastfeeding on Child IQ
Steer, C. D., Smith, G. D., Emmett, P. M., Hibbeln, J. R., & Golding, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011570 · Cited by 134
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“TPH gene and serotonin transporter (5HTT) gene (SLC64A) were the focus of many mood disorder studies (Risch et al., 2009; Karg et al., 2011).”
Duncan, L. E., Pollastri, A. R., & Smoller, J. W. (2014) · American Psychologist · doi:10.1037/a0036320 · Cited by 145
“This interaction was not supported in the two meta-analyses that used stringent inclusion criteria, an approach that provides the best test of the validity of the originally reported interaction (Munafò, Durrant, Lewis, & Flint, 2009; Risch et al., 2009).”
BackgroundArnau‐Soler, A., Macdonald-Dunlop, E., Adams, M. J., Clarke, T., MacIntyre, D. J., Milburn, K., Navrady, L. B., Scotland, G., Hayward, C., McIntosh, A. M., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0360-y · Cited by 139
Musliner, K. L., Seifuddin, F., Judy, J., Pirooznia, M., Goes, F. S., & Zandi, P. P. (2014) · Psychological Medicine · doi:10.1017/s0033291714002839 · Cited by 130
“Numerous attempts to replicate this finding over the past 10 years have yielded inconsistent results, however (Munafò et al. 2009; Risch et al. 2009; Karg et al. 2011), which led to a great deal of discourse and conflicting opinions surrounding the validity or exact nature of this association (Brown & Harris, 2008; Ca…”
ResultChildhood and Adolescent Anxiety and Depression: Beyond Heritability
Franić, S., Middeldorp, C. M., Dolan, C. V., Ligthart, L., & Boomsma, D. I. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.05.013 · Cited by 131
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Hankin, B. L., Nederhof, E., Oppenheimer, C. W., Jenness, J., Young, J. F., Abela, J. R. Z., Smolen, A., Ormel, J., & Oldehinkel, A. J. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.44 · Cited by 130
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Confirmatory and competitive evaluation of alternative gene‐environment interaction hypotheses
Belsky, J., Pluess, M., & Widaman, K. F. (2013) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12075 · Cited by 130
“This vantage-sensitivity-interaction hypothesis can easily be tested and contrasted with other GXE hypotheses – using the Widaman et al. (2012) approach – by fixing the cross-over point to the minimum end of the environmental variable and, in case of strong vantage sensitivity, constraining the slope of the vantage re…”
BackgroundMethodFox, E., Zougkou, K., Ridgewell, A., & Garner, K. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.07.004 · Cited by 135
“es (12), others find that as long as a detailed and comprehensive”
Duman, E. A., & Canli, T. (2015) · Biology of Mood & Anxiety Disorders · doi:10.1186/s13587-015-0017-x · Cited by 136
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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