Cited by 1,346Neurotransmitter Receptor Influence on BehaviorGenetic Associations and EpidemiologyStress Responses and Cortisol

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Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

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Caspi, Avshalom, Hariri, Ahmad R, Holmes, Andrew, Uher, Rudolf, Moffitt, Terrie E.·2010·American Journal of Psychiatry

DOI 10.1176/appi.ajp.2010.09101452PMC PMC2943341

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Abstract

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.

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“One explanation may be that girls with the 10/10 genotype are the most sensitive to environmental stress (Caspi et al., 2010), which resonates with sex differences in sensitivity to stressful events in human and non-human studies (Oldehinkel & Bouma, 2010).”
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Authors: Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E.
Affiliations: Duke University (US)
ORCID: Caspi, Avshalom
Hariri, Ahmad R
Holmes, Andrew
Uher, Rudolf
Moffitt, Terrie E.
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2010-05-01
Volume: 167
Issue: 5
Pages: 509-527
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.2010.09101452
PMC: PMC2943341
OpenAlex: W2100230238
Cited by: 1,346
References: 146
Citations by year: 2026: 7 · 2025: 24 · 2024: 29 · 2023: 26 · 2022: 20 · 2021: 59 · 2020: 81 · 2019: 60 · 2018: 55 · 2017: 90 · 2016: 97 · 2015: 130 · 2014: 114 · 2013: 150 · 2012: 186
FWCI: 15.86
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: American Journal of Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: National Institutes of Health
Economic and Social Research Council (ES/H034897/1)
National Institute on Alcohol Abuse and Alcoholism (ZIAAA000411)
National Institute on Aging (AG-032282, R01AG032282)
National Institute of Mental Health (MH-077874, R01MH077874, MH072837, K01MH072837)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD061298, R01HD061298)
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: gene-environment interaction, serotonin transporter gene, serotonin transporter, 5-HTTLPR, promoter polymorphism, stress sensitivity, depression, complex diseases, non-human primates, genetically engineered mouse models, construct validation, gene discovery, public understanding of genetics
MeSH terms: Animals, Brain, Depressive Disorder, Environment, Genotype, Humans, Models, Psychological, Primates, Stress, Psychological, Mood Disorders, Genetic Predisposition to Disease, Serotonin Plasma Membrane Transport Proteins, Genome-Wide Association Study

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Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

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