The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation.

Department of Human Genetics, University of Wuerzburg, Wuerzburg, Germany.
Archives of general psychiatry (Impact Factor: 13.75). 05/2011; 68(5):444-54. DOI: 10.1001/archgenpsychiatry.2010.189
Source: PubMed

ABSTRACT Two recent meta-analyses assessed the set of studies exploring the interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have assessed the relationship between 5-HTTLPR, stress, and depression.
To perform a meta-analysis including all relevant studies exploring the interaction.
We identified studies published through November 2009 in PubMed.
We excluded 2 studies presenting data that were included in other larger studies.
To perform a more inclusive meta-analysis, we used the Liptak-Stouffer z score method to combine findings of primary studies at the level of significance tests rather than the level of raw data.
We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (P = .00002). When stratifying our analysis by the type of stressor studied, we found strong evidence for an association between the s allele and increased stress sensitivity in the childhood maltreatment (P = .00007) and the specific medical condition (P = .0004) groups of studies but only marginal evidence for an association in the stressful life events group (P = .03). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafò et al studies, P = .16; Risch et al studies, P = .11). This suggests that the difference in results between meta-analyses was due to the different set of included studies rather than the meta-analytic technique.
Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that the studies published to date support the hypothesis that 5-HTTLPR moderates the relationship between stress and depression.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Resilience is a construct addressed in the psycho-oncology literature and is especially relevant to cancer survivorship. The purpose of this paper is to propose a model for resilience that is specific to adults diagnosed with cancer. To establish the proposed model, a brief review of the various definitions of resilience and of the resilience literature in oncology is provided. The proposed model includes baseline attributes (personal and environmental) which impact how an individual responds to an adverse event, which in this paper is cancer-related. The survivor has an initial response that fits somewhere on the distress-resilience continuum; however, post-cancer experiences (and interventions) can modify the initial response through a process of recalibration. The literature reviewed indicates that resilience is a common response to cancer diagnosis or treatment. The proposed model supports the view of resilience as both an outcome and a dynamic process. Given the process of recalibration, a discussion is provided of interventions that might facilitate resilience in adults with cancer. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Psycho-Oncology 03/2015; DOI:10.1002/pon.3800 · 4.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor.
    PLoS ONE 10(3):e0120685. DOI:10.1371/journal.pone.0120685 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology.
    PLoS ONE 10(3):e0119061. DOI:10.1371/journal.pone.0119061 · 3.53 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014