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

By N. Risch, R. Herrell, T. Lehner, K. Liang, Lindon J. Eaves, J. Hoh, Andrea Griem, M. Kovacs, J. Ott, Kathleen R. Merikangas. Journal of the American Medical Association (JAMA), 2009

1,748 citations recorded by the source corpus.

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, ≥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.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/2d01c4adeedd97c860f8f101b188992d634cf034

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Epidemiology

In Psychiatry and Mental health

Citations in the corpus

Neurobiological and psychiatric consequences of child abuse and neglect. (2010, result): “However, these results have not been uniformly replicated (Risch et al., 2009; Vergne & Nemeroff, 2006).”
Genetic Research in Psychiatry and Psychology (2010, background): “(Molecular genetic researcher Neil Risch et al., 2009, p. 2363) No patient, not a single one, has ever benefited from genetic research into mental illness, although many have been indirectly harmed by it (because it has discouraged the development of adequate services for patients and, during one…”
Measuring the suicidal mind: implicit cognition predicts suicidal behavior (2010, result): “, 2003) and because many of these results have failed to replicate (Risch et al., 2009).”
The origins and current status of behavioral activation treatments for depression. (2011, background): “The assertion continues to be supported empirically (Lewinsohn et al. 1994, Risch et al. 2009).”
Beyond diathesis stress: differential susceptibility to environmental influences. (2009, background): “…groups have attempted to replicate Caspi et al.'s (2003) findings of increased vulnerability to depression in response to stressful life events for individuals with one or more copies of the s allele; many have succeeded (see below) but certainly not all (Risch et al., 2009; Surtees et al., 2006).”
Differential Susceptibility to Environmental Influences (2013, background): “…have attempted to replicate Caspi et al.’s (2003) findings of increased vulnerability to depression in response to stressful life events for individuals with one or more copies of the s allele, with many succeeding (see below), but certainly not all (e.g., Surtees et al., 2006; Risch et al., 2009).”
Differential susceptibility to the environment: An evolutionary–neurodevelopmental theory (2011, background): “In addition, even if one considered the meta-analytic null conclusion regarding life events, 5-HTTLPR, and depression to be true, that would not and could not provide a basis for casting doubt, as Risch et al. (2009) did on this basis, on all G E interaction research.”
Candidate Genes and Political Behavior (2012, background): “2003) (Chipman et al. 2007; Lewis et al. 2010; Power et al. 2010; Surtees et al. 2006; Risch et al. 2009; Hoehe et al. 1998) (Hayden et al.”
A Genome-Wide Analysis of Liberal and Conservative Political Attitudes (2011, background): “However, a recent meta-analysis provided evidence that Caspi’s results do not withstand empirical validation (see Risch et al.2009).”
“The Biological Effects of Childhood Trauma” (2014, positive): “analyses that have found that adverse childhood events had a main effect on depressive outcomes regardless of 5-HTTLPR polymorphisms.(157,158) The discrepant findings in adults may be caused by failure to include trauma versus a stressful life event,”
Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. (2016, background): “Reprinted by permission fromMacmillan Publishers. appeared (e.g., Laucht et al., 2009) including a widely publicized meta-analysis (Risch et al., 2009) that concluded that there is no evidence that the serotonin transporter alone or in combination with stressful life events increases risk for…”