Cited by 1,655Neurotransmitter Receptor Influence on BehaviorGenetic Associations and EpidemiologyStress Responses and Cortisol

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Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

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Risch, Neil, Herrell, Richard, Lehner, Thomas, Liang, Kung-Yee, Eaves, Lindon, Hoh, Josephine, Griem, Andrea, Kovacs, Maria, Ott, Jurg, Merikangas, Kathleen Ries·2009·JAMA

DOI 10.1001/jama.2009.878PMC PMC2938776

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Abstract

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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BackgroundInfluential
Replicating 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
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Method
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Background
The serotonin transporter linked polymorphic region and brain-derived neurotrophic factor valine to methionine at position 66 polymorphisms and maternal history of depression: Associations with cognitive vulnerability to depression in childhood
Hayden, E. P., Olino, T. M., Bufferd, S. J., Miller, A., Dougherty, L. R., Sheikh, H. I., Singh, S. M., & Klein, D. N. (2013) · Development and Psychopathology · doi:10.1017/s0954579413000035 · Cited by 17
Molecular and Genetic Bases of Mammalian Maternal Behavior
Fleming, A. S., & Kraemer, G. W. (2019) · Gender and the Genome · doi:10.1177/2470289719827306 · Cited by 16
“Although DA, OT, and 5HT are implicated in major depression, the 5HT system seems to take precedence, likely in conjunction with the other systems in different aspects or symptoms of depression.(155-158) In fact, DAergic agents appear particularly useful as adjunct treatments targeting hedonic processes and the qualit…”
Background
The Molecular Genetics of Life Satisfaction: Extending Findings from a Recent Genome-Wide Association Study and Examining the Role of the Serotonin Transporter
Lachmann, B., Doebler, A., Sindermann, C., Sariyska, R., Cooper, A. J., Haas, H., & Montag, C. (2020) · Journal of Happiness Studies · doi:10.1007/s10902-020-00231-x · Cited by 15
“We will focus on the 5-HTTLPR polymorphism since several studies have suggested it could play an important role relating to mental well-being (e.g. Canli and Lesch 2007; De Neve 2011; De Neve et al. 2012; Murakami et al. 1999; Risch et al. 2009).”
Method
Epidemiological fallacies of modern psychiatric research
Newson, R. S., Karlsson, H., & Tiemeier, H. (2011) · Nordic Journal of Psychiatry · doi:10.3109/08039488.2010.539268 · Cited by 12
Neural signatures of the interaction between the 5-HTTLPR genotype and stressful life events in healthy women
Favaro, A., Manara, R., Pievani, M., Clementi, M., Forzan, M., Bruson, A., Tenconi, E., Degortes, D., Pinato, C., Giannunzio, V., et al. (2014) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2014.05.006 · Cited by 15
Early predictors of behavioural problems in pre-schoolers – a longitudinal study of constitutional and environmental main and interaction effects
Agnafors, S., Sydsjö, G., Comasco, E., Bladh, M. K., Oreland, L., & Svedin, C. G. (2016) · BMC Pediatrics · doi:10.1186/s12887-016-0614-x · Cited by 16
“Discordant results of gene-by environment effects related to both 5-HTTLPR and BDNF Val66Met polymorphisms have been found [16–18].”
Background
Effects of stress on functional connectivity during verbal processing
Nair, N., Hegarty, J. P., Ferguson, B. J., Hooshmand, S., Hecht, P. M., Tilley, M. R., Christ, S. E., & Beversdorf, D. Q. (2019) · Brain Imaging and Behavior · doi:10.1007/s11682-019-00221-5 · Cited by 15
Pharmacogenomic Biomarkers: Validation Needed for both the Molecular Genetic Mechanism and Clinical Effect
Sadée, W. (2011) · Pharmacogenomics · doi:10.2217/pgs.11.23 · Cited by 14
War exposure, 5-HTTLPR genotype and lifetime risk of depression
Artéro, S., Touchon, J., Dupuy, A., Malafosse, A., & Ritchie, K. A. (2011) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.110.087924 · Cited by 15
The Gene–Culture Interaction Framework and Implications for Health
Sasaki, J. Y., Leclair, J., West, A. L., & Kim, H. S. (2016) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780199357376.013.20 · Cited by 14
“…promoter region increases the likelihood of showing depressive symptoms compared to carrying the long (l) allele, but only when coupled with exposure to life stress (for recent meta-analytic support of this G × E finding, see Karg, Burmeister, Shedden, & Sen, 2011; but see also Risch et al., 2009).”
Background
The Generalized Pathology of Our Era: Comparing the Biomedical Explanation, the Cultural-Political Explanation, and a Liberal-Humanistic-Postmodernist Perspective
Ratner, C. (2017) · International Critical Thought · doi:10.1080/21598282.2017.1287586 · Cited by 14
“(Risch et al. 2009, 2463)13 Abnormal, economic crises are similarly the direct and logical outcome of pathologicalnormal economic/financial practices.”
Background
Recommendations for Abnormal Behaviour Ethograms in Monkey Research
Polanco, A., McCowan, B., Niel, L., Pearl, D. L., & Mason, G. J. (2021) · Animals · doi:10.3390/ani11051461 · Cited by 15
“From a welfare perspective, this posture is concerning since it may reflect a depressive‐ like state, sharing a similar etiology with human depression [21,22], including chronic stress (e.”
Background
Candidate Gene and Genome-Wide Association Studies in Behavioral Medicine
Nolte, I. M., McCaffery, J. M., & Snieder, H. (2010) · Springer eBooks · doi:10.1007/978-0-387-09488-5_29 · Cited by 14
Maternal Depression and Child and Adolescent Depression Symptoms: An Exploratory Test for Moderation by CRHR1, FKBP5 and NR3C1 Gene Variants
Lewis, G., Collishaw, S., Harold, G. T., Rice, F. J., & Thapar, A. (2011) · Behavior Genetics · doi:10.1007/s10519-011-9482-1 · Cited by 14
Association between serotonin transporter promoter polymorphisms and psychological distress in a diabetic population
Wilhelm, K. A., Gillis, I., Reddy, J., Mitchell, P. B., Campbell, L. V., Dobson‐Stone, C., Pierce, K. D., & Schofield, P. R. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.07.008 · Cited by 14
“The differences between the results based on the two methods of genotype classification may be considered in light of the recent debate over the robustness of the g e interaction (Munafo et al., 2009; Risch et al., 2009; Caspi et al., 2010; Karg et al., 2011).”
Method
Depression in systemic lupus erythematosus patients is associated with link-polymorphism but not methylation status of the 5HTT promoter region
Xu, J., Yq, C., Chen, B., Bai, R., Li, S., Xf, X., Xu, L., Jf, W., Lu, Z., & Xf, Z. (2013) · Lupus · doi:10.1177/0961203313498793 · Cited by 14
Interaction Between 5-HTTLPR Polymorphism and Abuse History on Adolescent African-American Females’ Condom Use Behavior Following Participation in an HIV Prevention Intervention
Sales, J. M., DiClemente, R. J., Brody, G. H., Philibert, R. A., & Rose, E. (2013) · Prevention Science · doi:10.1007/s11121-013-0378-6 · Cited by 14
“…suggested to have higher rates of depression or depressive symptoms, although there has been debate about the extent to which 5-HTTLPR moderates the association between stress and depression (see Risch et al. 2009 and Karg, Burmeister, Shedden and Sen 2011 for recent meta-analyses on the topic).”
No association between the serotonin transporter gene polymorphism 5-HTTLPR and cyclothymic temperament as measured by TEMPS-A
Landaas, E. T., Johansson, S., Halmøy, A., Oedegaard, K. J., Fasmer, O. B., & Haavik, J. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.08.028 · Cited by 14
Social constraints, genetic vulnerability, and mental health following collective stress
Holman, E. A., Lucas‐Thompson, R. G., & Lu, T. (2011) · Journal of Traumatic Stress · doi:10.1002/jts.20671 · Cited by 15
“…(Koenen et al., 2009; Taylor et al., 2006), while rendering individuals in high-risk social environments more vulnerable to depression and/or PTSD (Caspi et al., 2003; Kilpatrick et al., 2007, Taylor et al., 2006), though these findings have recently been challenged (Risch et al., 2009).”
Background
5‐HTTLPR moderates the relation between changes in depressive and bulimic symptoms in adolescent girls: A longitudinal study
Mata, J., & Gotlib, I. H. (2010) · International Journal of Eating Disorders · doi:10.1002/eat.20850 · Cited by 14
PTPRR regulates ERK dephosphorylation in depression mice model
Li, X., Liu, Z., Li, W., Sun, N., Xu, Y. J., Xie, Z., & Zhang, K. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.12.049 · Cited by 14
High frequency stimulation of the infralimbic cortex induces morphological changes in rat hippocampal neurons
Bezchlibnyk, Y. B., Stone, S. S. D., Hamani, C., & Lozano, A. M. (2016) · Brain stimulation · doi:10.1016/j.brs.2016.11.013 · Cited by 16
Influence of Serotonin Transporter SLC6A4 Genotype on the Effect of Psychosocial Stress on Cognitive Performance: An Exploratory Pilot Study
Beversdorf, D. Q., Carpenter, A. L., Alexander, J., Jenkins, N. T., Tilley, M. R., White, C. A., Hillier, A. J., Smith, R. M., & Gu, H. H. (2018) · Cognitive and Behavioral Neurology · doi:10.1097/wnn.0000000000000153 · Cited by 15
A comprehensive assessment of personality traits and psychosocial functioning in parents with bipolar disorder and their intimate partners
Serravalle, L., Iacono, V., Hodgins, S., & Ellenbogen, M. A. (2020) · International Journal of Bipolar Disorders · doi:10.1186/s40345-019-0172-x · Cited by 14
“Only negative dependent and independent life events were utilized due to their associations with mental illness (Kendler et al., 2010; Risch et al., 2009).”
Method
Genetics and education: Toward a genetically sensitive classroom.
Haworth, C. M. A., & Plomin, R. J. (2011) · American Psychological Association eBooks · doi:10.1037/13273-018 · Cited by 15
Developmental Issues in Assessment, Taxonomy, and Diagnosis of Psychopathology: Life Span and Multicultural Perspectives
Achenbach, T. M., & Rescorla, L. A. (2016) · Wiley eBooks · doi:10.1002/9781119125556.devpsy102 · Cited by 14
How Are Genes Related to Culture? An Introduction to the Field of Cultural Genomics
Causadías, J. M., & Korous, K. M. (2017) · Wiley eBooks · doi:10.1002/9781119181361.ch7 · Cited by 14
Depressive symptoms in adolescence: The role of perceived parental support, psychological control, and proactive control in interaction with 5-HTTLPR
Van Assche, E., Moons, T., Van Leeuwen, K., Colpin, H., Verschueren, K., Van Den Noortgate, W., Goossens, L., & Claes, S. (2016) · European Psychiatry · doi:10.1016/j.eurpsy.2016.01.2428 · Cited by 13
Associations of the serotonin transporter gene polymorphism, 5-HTTLPR, and adverse life events with late life depression in the elderly Lithuanian population
Šimonytė, S., Grabauskytė, I., Macijauskienė, J., Lesauskaitė, V., Lesauskaitė, V., Kvaal, K. S., & Stewart, R. J. (2023) · Scientific Reports · doi:10.1038/s41598-023-40215-4 · Cited by 19
Prediction of serotonin transporter promoter polymorphism genotypes from single nucleotide polymorphism arrays using machine learning methods
Lu, A. T.-H., Bakker, S. C., Janson, E., Cichon, S., Cantor, R. M., & Ophoff, R. A. (2012) · Psychiatric Genetics · doi:10.1097/ypg.0b013e328353ae23 · Cited by 13
“However, a recent meta-analysis failed to establish a genetic association of psychiatric illness (Risch et al. , 2009) with this polymorphism.”
Background
A Genetic Variant in 12q13, a Possible Risk Factor for Bipolar Disorder, Is Associated with Depressive State, Accounting for Stressful Life Events
Shimasaki, A., Kondo, K., Saito, T., Esaki, K., Otsuka, Y., Mano, K., Ikeda, M., & Iwata, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115135 · Cited by 13
“Although multiple meta-analyses of gene– environment (G6E) interactions between 5-HTTLPR and SLEs have not shown significant associations with MDD [9, 10, 11], little is known about other genes that may interact with SLEs.”
BackgroundMethodResult
Preliminary evidence for the interaction of the oxytocin receptor gene (oxtr) and face processing in differentiating prenatal smoking patterns
Massey, S. H., Estabrook, R., O’Brien, T. C., Pine, D. S., Burns, J. L., Jacob, S., Cook, E. H., & Wakschlag, L. S. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.10.049 · Cited by 13
Role of the cAMP–PKA–CREB–BDNF pathway in abnormal behaviours of serotonin transporter knockout mice
Wang, X., Wang, K., Wu, X., Huang, W., & Yang, L. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113681 · Cited by 13
Adolescent Loneliness and the Interaction between the Serotonin Transporter Gene (5-HTTLPR) and Parental Support: A Replication Study
Spithoven, A. W. M., Bijttebier, P., Noortgate, W. V. D., Colpin, H., Verschueren, K., Leeuwen, K. G. V., Claes, S. J., & Goossens, L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0133430 · Cited by 13
Epidemiology and inequalities
Bhugra, D., & Gupta, S. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511760990.004 · Cited by 13
Contemporary Genetics for Gender Researchers
Salk, R. H., & Hyde, J. S. (2012) · Psychology of Women Quarterly · doi:10.1177/0361684312461774 · Cited by 14
“Although some researchers have questioned the validity of these 5HTTLPR findings (e.g., Munafò, Durrant, Lewis, & Flint, 2009; Risch et al., 2009), the most recent and comprehensive meta-analysis to date supports the hypothesis that 5HTTLPR moderates the relationship between stress and depression (Karg, Burmeister, Sh…”
Result
Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression
Dawson, N., Ferrington, L., Lesch, K., & Kelly, P. A. T. (2010) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2010.10.006 · Cited by 14
Genetics of Stress: Gene–Stress Correlation and Interaction
Manuck, S. B., & McCaffery, J. M. (2010) · Springer eBooks · doi:10.1007/978-0-387-09488-5_31 · Cited by 14
No association between the serotonin transporter linked polymorphic region polymorphism and severity of posttraumatic stress disorder symptoms in combat veterans with or without comorbid depression
Petrović, Z. K., Erjavec, G. N., Perković, M. N., Peraica, T., & Pivac, N. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2016.08.017 · Cited by 13
The role of early adversity and recent life stress in depression severity in an outpatient sample
Vogt, D., Waeldin, S., Hellhammer, D. H., & Meinlschmidt, G. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.08.007 · Cited by 16
“Furthermore, as recent stressful life events have been shown to be associated with higher depression everity (Goodyer et al., 2000; Risch et al., 2009; e.g. Michl et al., 2013; Shapero t al., 2014), we additionally performed mediation analyses to analyze if possible associatins between pre- and /…”
Background
Father absence, age at menarche, and sexual behaviors in women: Evaluating the genetic confounding hypothesis using the androgen receptor gene.
Schlomer, G. L., Murray, J. L., Yates, B., Hair, K. L., & Vandenbergh, D. J. (2018) · Evolutionary Behavioral Sciences · doi:10.1037/ebs0000137 · Cited by 13
Differences in Sensitivity to Environment Depending on Catechol-O-Methyltransferase (COMT) Gene? A Meta-analysis of Child and Adolescent Gene-by-Environment Studies
Cao, C., Cao, L., & Chen, J. (2019) · Journal of Youth and Adolescence · doi:10.1007/s10964-019-01004-3 · Cited by 12
5-HTTLPR polymorphism and depression risk in Parkinson's disease: an updated meta-analysis
Cheng, P., Zhang, J., Wu, Y. H., Liu, W., Zhu, J., Chen, Z., Zhang, J., Guan, S., Sun, Y., & Wang, J. (2020) · Acta Neurologica Belgica · doi:10.1007/s13760-020-01342-1 · Cited by 13
Epidemiologie psychischer Störungen
Jacobi, F., & Kessler-Scheil, S. (2013) · Psychotherapeut · doi:10.1007/s00278-013-0962-z · Cited by 13
“Dies sprach f€ur eine Gen-UmweltInteraktion, in der Personen mit ihrer individuellen genetischen Ausstattung unterschiedlich auf stressreiche Ereignisse reagieren – allerdings konnten die Ergebnisse dieser ausgesprochen populären Studie später nur eingeschränkt repliziert werden (Risch et al. 2009).”
Background
Nature–Nurture Integration
Rutter, M. L. (2014) · Springer eBooks · doi:10.1007/978-1-4614-9608-3_3 · Cited by 13
“Genes of Happiness and Well Being” in the Context of Search Activity Concept
Rotenberg, V. S. (2013) · Activitas Nervosa Superior · doi:10.1007/bf03379593 · Cited by 14
“A meta-analysis of many investigations of interaction between the serotonin transporter gene (5-HTTLPR), stressfu l life events and risk of depression (Risch et al., 2009) have shown that only the number of stressful life events was significantly associated with depression.”
Background
The Interplay of Genetics, Behavior, and Pain with Depressive Symptoms in the Elderly
Klinedinst, N. J., Resnick, B. M., Yerges‐Armstrong, L. M., & Dorsey, S. G. (2015) · The Gerontologist · doi:10.1093/geront/gnv015 · Cited by 11
Environmental risk factors for psychopathology.
Schlossberg, K., Massler, A., & Zalsman, G. (2010) · PubMed · Cited by 13

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)
ORCID: Risch, Neil
Lehner, Thomas
Merikangas, Kathleen Ries
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2009-06-17
Volume: 301
Issue: 23
Pages: 2462
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2009.878
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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Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

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