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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Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
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BackgroundInfluential
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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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[14]Gene X environment interactions and developmental psychopathology National Institute of Mental Health Workshop Research Challenges and Opportunities June 27 28 2006 Washington, DC
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Interaction between genetic variants and exposure to Hurricane Katrina on post-traumatic stress and post-traumatic growth: A prospective analysis of low income adults
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“…(5-HTTLPR) located in the promoter region of the serotonin transporter gene (SLC6A4) has been commonly studied in GxE research (Caspi et al., 2003; Risch et al., 2009; Karg et al., 2011; Dunn et al., 2011) and consists of a short (S; 16 repeats) and long allele (L; 18 repeats); 5HTTLPR has been…”
Background
Public interest in predictive genetic testing, including direct-to-consumer testing, for susceptibility to major depression: preliminary findings
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Jasinska, A. J., Lowry, C. A., & Burmeister, M. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.01.001 · Cited by 95
Prenatal Stress, Maternal Immune Dysregulation, and Their Association With Autism Spectrum Disorders
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“More specifically, the diathesis-stress model proposes that traits regulated by the genome determine individual responsiveness to life-event stressors (Caspi and Moffitt, 2006; Pryce and Klaus, 2013; Risch et al., 2009).”
ADCYAP1R1GENOTYPE, POSTTRAUMATIC STRESS DISORDER, AND DEPRESSION AMONG WOMEN EXPOSED TO CHILDHOOD MALTREATMENT
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Therapygenetics: Using genetic markers to predict response to psychological treatment for mood and anxiety disorders
Lester, K. J., & Eley, T. C. (2013) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-3-4 · Cited by 95
“Individuals with the low expression short (S) allele of the 5HTTLPR report significantly more depressive symptoms when exposed to recent SLEs or childhood maltreatment relative to those with the long (L) allele (see [25] but also [26,27] for contradictory findings).”
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P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts
Soronen, P., Mantere, O., Melartin, T. K., Suominen, K. H., Vuorilehto, M. S., Rytsälä, H. J., Arvilommi, P., Holma, I. A. K., Holma, M., Jylhä, P. J., et al. (2011) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31179 · Cited by 92
Gene–environment interplay
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Multi-environment fitness landscapes of a tRNA gene
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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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