June 17, 2009

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

Author Affiliations

Author Affiliations: Institute for Human Genetics, University of California at San Francisco, and Kaiser Permanente Northern California Division of Research, Oakland (Dr Risch); Genetic Epidemiology Research Branch, National Institute of Mental Health, Bethesda, Maryland (Drs Herrell, Lehner, and Merikangas and Ms Griem); Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (Dr Liang); Departments of Human Genetics and Psychiatry, Virginia Commonwealth University, Richmond (Dr Eaves); Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, Connecticut (Dr Hoh); Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Kovacs); and Laboratory of Statistical Genetics, Rockefeller University, New York, NY (Dr Ott).

JAMA. 2009;301(23):2462-2471. doi:10.1001/jama.2009.878

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.