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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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“Gene by environment interplay involving the serotonin transporter is a fundamental finding in relation to mood disorders (Karg et al., 2011; Risch et al., 2009; Uher and McGuffin, 2008, 2010).”
BackgroundA direct test of the diathesis-stress model for depression
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Colodro-Conde, L., Couvy-Duchesne, B., Zhu, G., Coventry, W. L., Byrne, E. M., Gordon, S., Wright, M. J., Montgomery, G. W., Madden, P. A. F., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.130 · Cited by 285
Self-citationA genetic determinant of the striatal dopamine response to alcohol in men
Ramchandani, V. A., Umhau, J. C., Pavón, F. J., Ruiz-Velasco, V., Margas, W., Sun, H., Damadzic, R., Eskay, R. L., Schoor, M., Thorsell, A., et al. (2010) · Molecular Psychiatry · doi:10.1038/mp.2010.56 · Cited by 298
Adolescence: what do transmission, transition and translation have to do with it?
Casey, B. J., Duhoux, S., & Cohen, M. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.033 · Cited by 297
Gene-Environment Interaction in Psychological Traits and Disorders
Dick, D. M. (2011) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-032210-104518 · Cited by 311
The role of diet in the aetiopathogenesis of inflammatory bowel disease
Khalili, H., Chan, S. S. M., Lochhead, P. J., Ananthakrishnan, A. N., Hart, A. R., & Chan, A. T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0022-9 · Cited by 307
Gatt, J. M., Burton, K., Williams, L. M., & Schofield, P. R. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.09.014 · Cited by 281
Manuck, S. B., & McCaffery, J. M. (2014) · Annual Review of Psychology · doi:10.1146/annurev-psych-010213-115100 · Cited by 296
The relationship between chronotype and depressive symptoms: a meta-analysis
Au, J., & Reece, J. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.04.021 · Cited by 297
Bright-Light Therapy in the Treatment of Mood Disorders
Pail, G., Huf, W., Pjrek, E., Winkler, D., Willeit, M., Praschak-Rieder, N., & Kasper, S. F. (2011) · Neuropsychobiology · doi:10.1159/000328950 · Cited by 291
Gene-environment interaction and psychiatric disorders: Review and future directions
Assary, E., Vincent, J. P., Keers, R., & Pluess, M. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.10.016 · Cited by 295
The Genetic Basis of Addictive Disorders
Ducci, F., & Goldman, D. (2012) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2012.03.010 · Cited by 303
Dissecting diagnostic heterogeneity in depression by integrating neuroimaging and genetics
Buch, A. M., & Liston, C. M. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00789-3 · Cited by 289
“It has also been associated with neuroticism [128] and increased susceptibility to depression in response to stressful life events in some epidemiological cohorts and studies [129, 130] but not in others [131].”
BackgroundChild physical abuse and adult mental health: A national study
Sugaya, L. S., Hasin, D. S., Olfson, M., Lin, K., Grant, B. F., & Blanco, C. (2012) · Journal of Traumatic Stress · doi:10.1002/jts.21719 · Cited by 273
“Some of these results, however, are still controversial as suggested by a recent meta-analysis that found no significant association between the serotonin transporter gene 5-HTTLPR, stressful life events, and risk for depression (Risch et al., 2009).”
ResultThe solute carrier 6 family of transporters
Bröer, S., & Gether, U. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01975.x · Cited by 277
“The general significance of the promoter variant (5HTTLPR) has been debated (Munafo et al., 2009; Risch et al., 2009).”
BackgroundHigh anxiety trait: A vulnerable phenotype for stress-induced depression
Weger, M., & Sandi, C. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.01.012 · Cited by 289
Gene–environment interactions: early life stress and risk for depressive and anxiety disorders
Nugent, N. R., Tyrka, A. R., Carpenter, L. L., & Price, L. H. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2151-x · Cited by 269
“Although no published meta-analyses have focused on gene by ELS interactions, 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).”
BackgroundNaismith, S. L., Norrie, L. M., Mowszowski, L., & Hickie, I. B. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.05.009 · Cited by 282
Cultural Neuroscience: Biology of the Mind in Cultural Contexts
Kim, H. S., & Sasaki, J. Y. (2013) · Annual Review of Psychology · doi:10.1146/annurev-psych-010213-115040 · Cited by 285
Juster, R.-P., Bizik, G., Picard, M., Arsenault-Lapierre, G., Sindi, S., Trepanier, L., Marin, M.-F., Wan, N., Sekerovic, Z., Lord, C., et al. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000289 · Cited by 268
Transmission and Prevention of Mood Disorders Among Children of Affectively Ill Parents: A Review
Beardslee, W. R., Gladstone, T. R. G., & O’Connor, E. (2011) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2011.07.020 · Cited by 294
Bakermans‐Kranenburg, M. J., & van IJzendoorn, M. H. (2014) · Annual Review of Psychology · doi:10.1146/annurev-psych-010814-015407 · Cited by 288
“…of the association between depression and life events, with the risk of depression increasing with the number of life events among those with the short (ss or sl ) 5-HTT genotype and decreasing with the number of life events among those with the long (ll ) genotype (Risch et al. 2009, p. 2469).”
Backgroundvan IJzendoorn, M. H., Caspers, K., Bakermans-Kranenburg, M. J., Beach, S. R. H., & Philibert, R. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.05.008 · Cited by 264
Zimmermann, P., Brückl, T., Nocon, A., Pfister, H., Binder, E. B., Uhr, M., Lieb, R., Moffitt, T. E., Caspi, A., Holsboer, F., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10111577 · Cited by 262
Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder
Nigg, J., Nikolas, M., & Burt, S. A. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.01.025 · Cited by 259
Cognitive aspects of depression
Kircanski, K., Joormann, J., & Gotlib, I. H. (2012) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1177 · Cited by 279
Classification of trauma and stressor-related disorders in DSM-5
Friedman, M. J., Resick, P. A., Bryant, R. A., Strain, J. J., Horowitz, M. J., & Spiegel, D. (2011) · Depression and Anxiety · doi:10.1002/da.20845 · Cited by 254
Brummelte, S., Mc Glanaghy, E., Bonnin, A., & Oberlander, T. F. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2016.02.037 · Cited by 306
“Early life experiential variables influence susceptibility to environmental factors (Caspi and Moffitt, 2006; Moffitt et al., 2005) and not all outcomes associated with the short allele are necessarily negative (Risch et al., 2009).”
Serotonin and beyond: therapeutics for major depression
Blier, P., & Mansari, M. E. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2012.0536 · Cited by 271
“Although this claim has been challenged [11], the analysis of all 54 studies, instead of subsamples, confirmed this important link [12].”
ResultMicroglia: An Interface between the Loss of Neuroplasticity and Depression
Singhal, G., & Baune, B. T. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00270 · Cited by 261
“In spite of observed anatomic and physiologic changes in brain, no conclusive proof has been found linking any combination of genetic and environmental factors (aan het Rot et al., 2009; Risch et al., 2009).”
BackgroundDNA methylation: A mechanism for embedding early life experiences in the genome
Szyf, M., & Bick, J. (2013) · Child Development · doi:10.1111/j.1467-8624.2012.01793.x · Cited by 251
“Although the interaction between genotypes and environmental conditions has been an exciting possibility, there is significant controversy regarding the replicability of these original findings (Risch et al., 2009).”
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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