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

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

1,394 citations recorded by the source corpus.

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 (G×E) 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 G×E research. The authors discuss how G×E interaction hypotheses can be tested with large and small samples, how G×E research can be carried out before as well as after replicated gene discovery, the uses of G×E research as a tool for gene discovery, the importance of construct validation in evaluating G×E research, and the contribution of G×E research to the public understanding of genetic science.

Subfields: Behavioral Neuroscience, Cellular and Molecular Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/aaa0eca6fb3a57572089985fc829f6237a02d25b

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Citations in the corpus

The Biological Implausibility of the Nature-Nurture Dichotomy & What It Means for the Study of Infancy (2011, background): “In sum, Caspi et al. (2010) point out that it is necessary to focus on a specific, homogeneous, developmentally relevant, and clearly operationalized depression-inducing events in order to decrease between-subject heterogeneity in exposure to such events and, thus, maximize the internal validity of…”
THE DETERMINANTS OF HUMAN CAPITAL FORMATION DURING THE EARLY YEARS OF LIFE: THEORY, MEASUREMENT, AND POLICIES (2015, background): “(2013) and Caspi et al. (2010).”
A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry (2011, positive): “Similarly, G×Es could provide compelling explanations for why one person becomes depressed in response to severe life stressors while another does not (1), or why cannabis use increases risk for psychosis in one person but not in another (2).”
Practitioner Review: What have we learnt about the causes of ADHD? (2013, background): “Emerging evidence is beginning to challenge the hypotheses that maternal stress and smoking in pregnancy are causal risk factors for ADHD, but further quasi-experimental research is needed.”
All for one and one for all: Mental disorders in one dimension (2018, background): “Finally, although maltreatment is a potent risk factor for developing psychiatric disorders, it is apparent that there are marked individual differences in response to it, andmany peoplewho are victimized remain healthy (110), suggesting stress sensitivity (a process distinct from stress sensitizati”
The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-Analysis Revisited: Evidence of Genetic Moderation (2011, methodology): “Potential studies were identified from previous meta-analyses and review articles and through PubMed at the National Library of Medicine, using the search terms depression or depressed and “serotonin transporter” or 5-HTTLPR and stress or maltreatment.(3,4,10) We subsequently checked the reference s”
Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression (2018, background): “, genotypes) and exogenous pharmacological inputs—such as drugs (Alexander et al., 1981; Caspi et al., 2010).”
Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. (2012, positive): “…suicide attempt, alcohol consumption, substance use, sleep disturbances, anxiety sensitivity, and impaired self-regulation of negative affect (Caspi et al., 2010), suggesting that a combination of 5-HTTLPR genotype and stressful life events or early trauma moderates the susceptibility to a…”