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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
Open accessAbstract
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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“Caspi et al. (2010), recently reviewing the role of 5-HTTLPR in stress sensitivity from a broader perspective, asserted a prominent role for this gene in the neurobiological and behavioral responses to stress.”
From Gene–environment interactions: early life stress and risk for depressive and anxiety disorders (2011) · cites this paper as Caspi et al. (2010)
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“Examination of continuous measures affords greater statistical power and may decrease statistical error due to miscategorization of “subthreshold” individuals (Caspi et al. 2010; Plomin and Davis 2009).”
From Gene–environment interactions: early life stress and risk for depressive and anxiety disorders (2011) · cites this paper as Caspi et al. 2010
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Metadata
- Authors
- Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E.
- Affiliations
- Duke University (US)
- Venue
- American Journal of Psychiatry
- Published
- 2010-05-01
- Volume
- 167
- Issue
- 5
- Pages
- 509-527
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- 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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