Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression
http://jama.ama-assn.org/cgi/content/short/301/23/2462
A Meta-analysis
Neil Risch, PhD; Richard Herrell, PhD; Thomas Lehner, PhD; Kung-Yee Liang, PhD; Lindon Eaves, PhD; Josephine Hoh, PhD; Andrea Griem, BS; Maria Kovacs, PhD; Jurg Ott, PhD; Kathleen Ries Merikangas, PhD
JAMA. 2009;301(23):2462-2471.
Context Substantial resources are being devoted to identifycandidate genes for complex mental and behavioral disordersthrough inclusion of environmental exposures following the reportof an interaction between the serotonin transporter linked polymorphicregion (5-HTTLPR) and stressful life events on an increasedrisk of major depression.
Objective To conduct a meta-analysis of the interactionbetween the serotonin transporter gene and stressful life eventson depression using both published data and individual-leveloriginal data.
Data Sources Search of PubMed, EMBASE, and PsycINFO databasesthrough March 2009 yielded 26 studies of which 14 met criteriafor the meta-analysis.
Study Selection Criteria for studies for the meta-analysesincluded published data on the association between 5-HTTLPRgenotype (SS, SL, or LL), number of stressful life events (0,1, 2, 
3) or equivalent, and a categorical measure of depressiondefined by the Diagnostic and Statistical Manual of Mental Disorders(Fourth Edition) or the International Statistical Classificationof Diseases, 10th Revision (ICD-10) or use of a cut point todefine depression from standardized rating scales. To maximizeour ability to use a common framework for variable definition,we also requested original data from all studies published priorto 2008 that met inclusion criteria. Of the 14 studies includedin the meta-analysis, 10 were also included in a second sex-specificmeta-analysis of original individual-level data.
Data Extraction Logistic regression was used to estimatethe effects of the number of short alleles at 5-HTTLPR, thenumber of stressful life events, and their interaction on depression.Odds ratios (ORs) and 95% confidence intervals (CIs) were calculatedseparately for each study and then weighted averages of theindividual 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 classifiedas having depression; 12 481 as not having depression.
Results In the meta-analysis of published data, the numberof stressful life events was significantly associated with depression(OR, 1.41; 95% CI,1.25-1.57). No association was found between5-HTTLPR genotype and depression in any of the individual studiesnor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) andno interaction effect between genotype and stressful life eventson depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparableresults were found in the sex-specific meta-analysis of individual-leveldata.
Conclusion This meta-analysis yielded no evidence thatthe serotonin transporter genotype alone or in interaction withstressful life events is associated with an elevated risk ofdepression in men alone, women alone, or in both sexes combined.
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).
