Meta-analyses of the 5-HTTLPR polymorphisms and post-traumatic stress disorder

PLoS One. 2013 Jun 25;8(6):e66227. doi: 10.1371/journal.pone.0066227. Print 2013.


Objective: To conduct a meta-analysis of all published genetic association studies of 5-HTTLPR polymorphisms performed in PTSD cases.

Methods data sources: Potential studies were identified through PubMed/MEDLINE, EMBASE, Web of Science databases (Web of Knowledge, WoK), PsychINFO, PsychArticles and HuGeNet (Human Genome Epidemiology Network) up until December 2011.

Study selection: Published observational studies reporting genotype or allele frequencies of this genetic factor in PTSD cases and in non-PTSD controls were all considered eligible for inclusion in this systematic review.

Data extraction: Two reviewers selected studies for possible inclusion and extracted data independently following a standardized protocol.

Statistical analysis: A biallelic and a triallelic meta-analysis, including the total S and S' frequencies, the dominant (S+/LL and S'+/L'L') and the recessive model (SS/L+ and S'S'/L'+), was performed with a random-effect model to calculate the pooled OR and its corresponding 95% CI. Forest plots and Cochran's Q-Statistic and I(2) index were calculated to check for heterogeneity. Subgroup analyses and meta-regression were carried out to analyze potential moderators. Publication bias and quality of reporting were also analyzed.

Results: 13 studies met our inclusion criteria, providing a total sample of 1874 patients with PTSD and 7785 controls in the biallelic meta-analyses and 627 and 3524, respectively, in the triallelic. None of the meta-analyses showed evidence of an association between 5-HTTLPR and PTSD but several characteristics (exposure to the same principal stressor for PTSD cases and controls, adjustment for potential confounding variables, blind assessment, study design, type of PTSD, ethnic distribution and Total Quality Score) influenced the results in subgroup analyses and meta-regression. There was no evidence of potential publication bias.

Conclusions: Current evidence does not support a direct effect of 5-HTTLPR polymorphisms on PTSD. Further analyses of gene-environment interactions, epigenetic modulation and new studies with large samples and/or meta-analyses are required.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Genetic Predisposition to Disease
  • Humans
  • Polymorphism, Genetic / genetics*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Stress Disorders, Post-Traumatic / genetics*


  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins

Grant support

This work has been financed by the Regional Health Authorities of Murcia (Consejería de Sanidad y Política Social and Servicio Murciano de Salud) and the Fundación para la Formación e Investigación Sanitaria (FFIS) of the Murcia Region. The funding agencies had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Jim van Os