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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“meta-analyses of the literature have been published, and they reach opposite conclusions: two found no evidence for an interaction [22,23] while one concluded that there was an effect [24].”
BackgroundPsychobiological differences between depression and somatization
Rief, W., Hennings, A., Riemer, S., & Euteneuer, F. (2010) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2010.02.001 · Cited by 85
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“Researchers have also reported that the boarding school experience increases the probability of depression and psychological distress for some youth (e.g., Midgley et al., 2017; Risch et al., 2009; Sanchez et al., 2012).”
BackgroundShao, X., & Zhu, G. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00381 · Cited by 91
Imaging genetics of mood disorders
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The Genetics of Major Depression
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“Two meta-analyses found no evidence for an interaction (Munafò et al., 2009; Risch et al., 2009), while one meta-analysis concluded that there was an effect (Karg et al.”
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Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory
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“Gene–social environment interactions have been proposed by a number of candidate gene studies [121–126], including an influential (although controversial; [127]) set of studies arguing that susceptibility to depression and antisocial behavioral disorders results from the combination of susceptible genotype and adverse…”
BackgroundAdvance in Stress for Depressive Disorder
Ding, Y., & Dai, J. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9271-0_8 · Cited by 86
The current state of play on the molecular genetics of depression
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“E 5HTTLPR studies published to date respectively (Munafò et al. 2009 ; Risch et al. 2009).”
MethodFabbri, C., Hosák, L., Mößner, R., Giegling, I., Mandelli, L., Bellivier, F., Claes, S. J., Collier, D. A., Corrales, A., DeLisi, L. E., et al. (2016) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2016.1208843 · Cited by 84
“A number of genetic studies investigated the effect of the 5-HTTLPR polymorphism on susceptibility to MDD, and two meta-analyses reported absent or negligible effects (Munafo et al. 2009; Risch et al. 2009).”
BackgroundEpigenetics applied to psychiatry: Clinical opportunities and future challenges
Kular, L., & Kular, S. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12634 · Cited by 90
Schulze, T. G. (2010) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2009.10.005 · Cited by 80
Gene–Environment Interactions and Intermediate Phenotypes: Early Trauma and Depression
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Serotonin transporter gene promoter region polymorphism and selective processing of emotional images
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Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update
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“Neiss, Rowe, & Rodgers (2002) Age at first birth 6% 20% M/F 31–39 NLSY79 4,612 Siblings Nationally representative Rodgers, Bard, & Miller (2007) Number of births by age 20 65% 9% F 20 NLSY79 1,198 Siblings Nationally representative”
BackgroundInfluentialPharmacogenomics of the RNA World: Structural RNA Polymorphisms in Drug Therapy
Sadée, W., Wang, D., Papp, A. C., Pinsonneault, J. K., Smith, R. M., Moyer, R. A., & Johnson, A. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2010.314 · Cited by 79
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5-HTTLPR and BDNF Val66Met polymorphisms moderate effects of stress on rumination
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A New Look at Core Emotional Needs
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“Although some have questioned the replicability of particular Gene 9 Environment (G9E) interactions that have appeared in the published literature (Duncan & Keller, 2011; Risch et al., 2009), it would certainly seem mistaken to throw the genetic-moderation-of-environmentalinfluences baby out with the bathwater (Caspi,…”
Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.8.3.foc398 · Cited by 79
Depression and stressful environments: identifying gaps in conceptualization and measurement
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“One group published a meta-analysis indicating nonsignificant evidence of gene × environment interactions with the serotonin promotor variant 5-HTTLPR (Risch et al., 2009), whereas another group’s larger meta-analysis resulted in analyses supporting evidence of gene– environment interaction with this gene (Karg, Burme…”
ResultPoor replication validity of biomedical association studies reported by newspapers
Dumas-Mallet, E., Smith, A., Boraud, T., & Gonon, F. (2017) · PLOS ONE · doi:10.1371/journal.pone.0172650 · Cited by 76
“Finally, the meta-analysis published in 2009 by Risch and coworkers in JAMA (IF = 30) and contradicting "positive" findings [29], was covered by only four newspaper articles and all four mentioned that the initial finding "has not held up to scientific scrutiny".”
BackgroundSocial Influences on Health: Is Serotonin a Critical Mediator?
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Ten-Eleven Translocation Proteins Modulate the Response to Environmental Stress in Mice
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“Among these causes, chronic stress in particular has been shown to result in decreased serotonin and other neurotransmitters in the brain and thus to be a direct link to depression (Caspi et al., 2003; Risch et al., 2009).”
BackgroundRisk and Adversity in Developmental Psychopathology
Obradović, J., Shaffer, A. E., & Masten, A. S. (2012) · Cambridge University Press eBooks · doi:10.1017/cbo9781139016827.004 · Cited by 91
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The Serotonin Transporter and Early Life Stress: Translational Perspectives
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“Multiple studies showing results against, but mostly in favor of this relationship have been performed (Munafò et al., 2009; Risch et al., 2009; Karg et al., 2011; McGuffin et al., 2011; Sharpley et al., 2014; Vrijsen et al., 2015).”
ResultFowler, J. H., & Dawes, C. T. (2013) · American Political Science Review · doi:10.1017/s0003055413000063 · Cited by 73
“Finally, it should be pointed out that a previously reported association between depression and an interaction of 5HTT and stressful life has not been reproduced by follow-up studies (Duncan and Keller 2011; Risch et al. 2009).”
Early Life Stress, Physiology, and Genetics: A Review
Fogelman, N., & Canli, T. (2019) · Frontiers in Psychology · doi:10.3389/fpsyg.2019.01668 · Cited by 79
5-HTTLPR and gender differences in affective disorders: A systematic review
Gressier, F., Calati, R., & Serretti, A. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.09.027 · Cited by 73
“In a meta-analysis on the interaction between 5-HTTLPR and SLE on depression, no association was reported for females alone, males alone and for all participants (Risch et al., 2009).”
BackgroundPost, R. M. (2016) · Bipolar Disorders · doi:10.1111/bdi.12401 · Cited by 78
Liu, Y., Zhou, X., Yang, L., Wang, H., Zhang, Y., Pu, J., Liu, L., Gui, S., Zeng, L., Chen, J., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0176725 · Cited by 75
Costafreda, S. G., McCann, P., Saker, P., Cole, J. H., Cohen‐Woods, S., FARMER, A. E., Aitchison, K. J., McGuffin, P., & Fu, C. H. Y. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.02.028 · Cited by 72
“The evidence, however, has been controversial: two recent meta-analyses that analysed a subset of all studies failed to identify a statistically significant effect of the S-allele, or of the interaction between genotype and life events in the risk of depression (Munaf o et al., 2009; Risch et al., 2009).”
ResultHomberg, J. R., & Jagiellowicz, J. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01047-8 · Cited by 76
Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders
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“Indeed, a meta-analysis reported a significant interaction between childhood maltreatment and the s allele genotype, which can increase the risk for depression later in life,(117) although negative results have been reported.(118) Discrepancies in the field could be linked to the timing of the gene-environment interac…”
BackgroundBrown, G. W., Ban, M., Craig, T., Harris, T., Herbert, J., & Uher, R. (2012) · Depression and Anxiety · doi:10.1002/da.21982 · Cited by 71
“First, reviews and meta-analyses have concluded that adult stressful events make at most a weak contribution to the G × E,[6, 7] but have supported the role of childhood maltreatment in this G × E.”
BackgroundResultCentral serotonin transporter levels are associated with stress hormone response and anxiety
Reimold, M., Knobel, A., Rapp, M. A., Batra, A., Wiedemann, K., Ströhle, A., Zimmer, A., Schönknecht, P., Smolka, M. N., Weinberger, D. R., et al. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1903-y · Cited by 72
Old Friends, immunoregulation, and stress resilience
Langgartner, D., Lowry, C. A., & Reber, S. O. (2018) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2228-7 · Cited by 76
Developing Civic Engagement within a Civic Context
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“The strong influence of adverse life events on the development of depression is also apparent in a meta-analysis conducted by Risch et al. (2009), where the only risk factor significantly correlated with depression was the occurrence of stressful life events.”
BackgroundMethodAquatic blues: Modeling depression and antidepressant action in zebrafish
Nguyen, M., Stewart, A., & Kalueff, A. V. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.03.003 · Cited by 72
Pang, C., Cao, L., Wu, F., Wang, L., Wang, G., Yu, Y., Zhang, M., Chen, L., Wang, W., Lv, W., et al. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.04.017 · Cited by 71
Heiming, R. S. (2009) · Frontiers in Behavioral Neuroscience · doi:10.3389/neuro.08.026.2009 · Cited by 73
Aas, M., Djurovic, S., Athanasiu, L., Steen, N. E., Agartz, I., Lorentzen, S., Sundet, K. S., Andreassen, O. A., & Melle, I. S. (2011) · Schizophrenia Bulletin · doi:10.1093/schbul/sbr113 · Cited by 73
Serotonin transporter gene and childhood trauma - a G × E effect on anxiety sensitivity
Klauke, B., Deckert, J., Reif, A., Pauli, P., Zwanzger, P., Baumann, C. R., Arolt, V., Glöckner-Rist, A., & Domschke, K. (2011) · Depression and Anxiety · doi:10.1002/da.20840 · Cited by 75
“In depression, there is cumulative, though not unequivocal evidence for the 5-HTTLPR S allele to increase sensitivity to (LEs), and thereby vulnerability to depression,[58,59] [but:[60]].”
BackgroundSasaki, J. Y., Kim, H. S., & Xu, J. (2011) · Journal of Cross-Cultural Psychology · doi:10.1177/0022022111412526 · Cited by 71
Depression is associated with enhanced aversive Pavlovian control over instrumental behaviour
Nord, C. L., Lawson, R. P., Huys, Q. J. M., Pilling, S., & Roiser, J. P. (2018) · Scientific Reports · doi:10.1038/s41598-018-30828-5 · Cited by 70
Brain connectivity in psychiatric imaging genetics
Tost, H., Bilek, E., & Meyer‐Lindenberg, A. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.11.007 · Cited by 72
“…or Risch et al. are recommended for further reading on the topic of inconsistencies in the literature, for they seem to question the association between 5- HTTLPR genotype, environmental stressors and risk for psychiatric disease (Clarke et al., 2010; Munafo et al., 2009; Risch et al., 2009).”
BackgroundFletcher, J. M., & Conley, D. (2013) · American Journal of Public Health · doi:10.2105/ajph.2013.301290 · Cited by 70
Mehta, D., Quast, C., Fasching, P., Seifert, A., Voigt, F., Beckmann, M., Faschingbauer, F., Burger, P., Ekici, A., Kornhuber, J., et al. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.11.042 · Cited by 68
“Many association studies investigating both direct associations of 5-HTTLPR with major depressive disorder (MDD) and interactions of 5-HTTLPR with stressful life events (SLEs) have resulted in inconsistent results probably due to themethodological heterogeneity in assessment of SLEs and sample recruitment (Caspi et al…”
ResultGenes, Eyeglasses, and Social Policy
Manski, C. F. (2011) · The Journal of Economic Perspectives · doi:10.1257/jep.25.4.83 · Cited by 70
Eker, M. C., Kitiş, Ö., Okur, H., Eker, Ö. D., Ozan, E., Işıklı, S., Akarsu, N. A., & Gönül, A. S. (2010) · Neuropsychobiology · doi:10.1159/000321834 · Cited by 70
Long-term exposure to residential greenness and decreased risk of depression and anxiety
Wang, J., Ma, Y., Tang, L., Li, D., Xie, J., Hu, Y., & Tian, Y. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00227-z · Cited by 75
Volition diminishes genetically mediated amygdala hyperreactivity
Schardt, D. M., Erk, S., Nüsser, C., Nöthen, M. M., Cichon, S., Rietschel, M., Treutlein, J., Goschke, T., & Walter, H. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.11.078 · Cited by 73
Socio-Genomic Research Using Genome-Wide Molecular Data
Conley, D. (2016) · Annual Review of Sociology · doi:10.1146/annurev-soc-081715-074316 · Cited by 72
“2011) or lack consistent supporting replication (Risch et al. 2009).”
BackgroundDepression in adolescence: A review
Beirão, D., Monte, H., Amaral, M., Longras, A., Matos, C., & Villas-Boas, F. (2020) · Middle East Current Psychiatry · doi:10.1186/s43045-020-00050-z · Cited by 70
“However, such findings seem to vary not only by genotype but also by age, sex, and severity of symptoms, and are also reliant on good quality measures of adversity and depression [18, 20].”
BackgroundBiosocial Influences on the Family: A Decade Review
D'Onofrio, B. M., & Lahey, B. B. (2010) · Journal of Marriage and the Family · doi:10.1111/j.1741-3737.2010.00729.x · Cited by 70
Genetic influences on cardiovascular stress reactivity
Wu, T., Snieder, H., & de Geus, E. J. C. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.12.001 · Cited by 68
The Genetics of Mood Disorders
Lau, J. Y. F., & Eley, T. C. (2009) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.121208.131308 · Cited by 71
Can we observe epigenetic effects on human brain function?
Nikolova, Y. S., & Hariri, A. R. (2015) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2015.05.003 · Cited by 73
Goodyer, I. M., Croudace, T., Dudbridge, F., Ban, M., & Herbert, J. (2010) · British Journal of Psychiatry · doi:10.1192/bjp.bp.110.077750 · Cited by 67
Integrating Social Science and Genetics: News from the Political Front
Hatemi, P., Dawes, C. T., Frost-Keller, A., Settle, J. E., & Verhulst, B. (2011) · Biodemography and Social Biology · doi:10.1080/19485565.2011.568276 · Cited by 66
Jones, K. L., Smith, R. M., Edwards, K. S., Givens, B. S., Tilley, M. R., & Beversdorf, D. Q. (2010) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2010.05.002 · Cited by 67
Bevilacqua, L. M., & Goldman, D. A. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.07.009 · Cited by 70
Social status and day-to-day behaviour of male serotonin transporter knockout mice
Lewejohann, L., Kloke, V., Heiming, R. S., Jansen, F., Kaiser, S., Schmitt, A. G., Lesch, K., & Sachser, N. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.03.035 · Cited by 68
A Review of the Conceptualisation and Risk Factors Associated with Treatment-Resistant Depression
Murphy, J., Sarris, J. J., & Byrne, G. J. (2017) · Depression Research and Treatment · doi:10.1155/2017/4176825 · Cited by 77
“However, a recent meta-analysis comprising 14 studies found no evidence of the serotonin transporter gene interacting with stressful life events to increase the risk of depression [47].”
BackgroundSerotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression
Antypa, N., & van der Does, W. A. J. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00593.x · Cited by 70
Mellman, T. A., Alim, T. N., Brown, D. D., Gorodetsky, E. K., Búzás, B., Lawson, W. B., Goldman, D. A., & Charney, D. S. (2009) · Depression and Anxiety · doi:10.1002/da.20627 · Cited by 66
Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game
Zhong, S., Israel, S., Shalev, I., Xue, H., Ebstein, R. P., & Chew, S. H. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013765 · Cited by 70
Bruwer, B., Govender, R., Bishop, M., Williams, D. R., Stein, D. J., & Seedat, S. (2014) · BMJ Open · doi:10.1136/bmjopen-2013-004644 · Cited by 73
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Boardman, J. D., Domingue, B. W., Blalock, C. L., Haberstick, B. C., Harris, K. M., & McQueen, M. B. (2013) · Demography · doi:10.1007/s13524-013-0259-4 · Cited by 65
“…environment, little agreement regarding statistical versus substantive significance of interactions, little consensus about social and genetic theories explaining the mechanisms of gene-environment interplay, and a replication record that is only marginally better than chance (Risch et al. 2009).”
BackgroundGene–Environment Interactions and Response to Social Intrusion in Male and Female Rhesus Macaques
Schwandt, M. L., Lindell, S. G., Sjöberg, R. L., Chisholm, K., Higley, J. D., Suomi, S. J., Heilig, M. A., & Barr, C. S. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.10.016 · Cited by 67
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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