Meta-analysis of the interaction between serotonin transporter promoter variant, stress, and posttraumatic stress disorder

Abstract

Exposure to stress predicts the occurrence of posttraumatic stress disorder (PTSD) in individuals harboring the serotonin transporter promoter variant 5-HTTLPR. We carried out a meta-analysis of studies investigating the interaction between 5-HTTLPR, stress, and PTSD to clarify the interrelatedness of these factors. We reviewed all relevant studies published in English before May 2016. The Lipták-Stouffer z-score method for meta-analysis was applied to combined data. The z score was separately calculated for the stressful life events, childhood adversity, bi- and triallelic loci, and cross-sectional and longitudinal studies subgroups. A total of 14 studies with 15,883 subjects met our inclusion criteria. We found strong evidence that the presence of 5-HTTLPR influenced the relationship between stress and PTSD (P = 0.00003), with the strongest effects observed in the cross-sectional and longitudinal groups (P = 0.01 and 2.0 × 10^-6, respectively). Stressful life events and childhood adversity separately interacted with 5-HTTLPR in PTSD (P = 2.0 × 10^-8 and 0.003, respectively). When the studies were stratified by locus classification, the evidence was stronger for the triallelic (P = 4.0 × 10^-8) than for the biallelic (P = 0.054) locus subgroup. There was strong evidence that 5-HTTLPR influences the relationship between stress and PTSD.

Figure 1

Flow chart of study screening process.

Figure 2

Forest plot of 14 human observational studies for the interaction of 5-HTTLPR genotype and life stress on PTSD. The squares mark indicate the one-tailed P value for each study, where lower values denote greater stress sensitivity of S allele carriers and higher values correspond to greater stress sensitivity of L allele carriers. The size of the box reflects relative sample size. The red triangle indicates the overall result of meta-analysis. Black squares mark studies that indexed stressful life events; Dark blue indicates childhood adversity; and light blue indicates studies that included both stressful life events and childhood adversities; The squares with red border indicate S/Lg alleles; The squares with blue border indicate S alleles; and the squares with purple border indicate La alleles. The squares with w-resize indicate longitudinal studies and the squares with e-resize indicate cross-sectional studies.