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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

ABSTRACT: The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38?802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

SUBMITTER: Culverhouse RC

PROVIDER: S-EPMC5628077 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

Culverhouse R C RC Saccone N L NL Horton A C AC Ma Y Y Anstey K J KJ Banaschewski T T Burmeister M M Cohen-Woods S S Etain B B Fisher H L HL Goldman N N Guillaume S S Horwood J J Juhasz G G Lester K J KJ Mandelli L L Middeldorp C M CM Olié E E Villafuerte S S Air T M TM Araya R R Bowes L L Burns R R Byrne E M EM Coffey C C Coventry W L WL Gawronski K A B KAB Glei D D Hatzimanolis A A Hottenga J-J JJ Jaussent I I Jawahar C C Jennen-Steinmetz C C Kramer J R JR Lajnef M M Little K K Zu Schwabedissen H M HM Nauck M M Nederhof E E Petschner P P Peyrot W J WJ Schwahn C C Sinnamon G G Stacey D D Tian Y Y Toben C C Van der Auwera S S Wainwright N N Wang J-C JC Willemsen G G Anderson I M IM Arolt V V Åslund C C Bagdy G G Baune B T BT Bellivier F F Boomsma D I DI Courtet P P Dannlowski U U de Geus E J C EJC Deakin J F W JFW Easteal S S Eley T T Fergusson D M DM Goate A M AM Gonda X X Grabe H J HJ Holzman C C Johnson E O EO Kennedy M M Laucht M M Martin N G NG Munafò M R MR Nilsson K W KW Oldehinkel A J AJ Olsson C A CA Ormel J J Otte C C Patton G C GC Penninx B W J H BWJH Ritchie K K Sarchiapone M M Scheid J M JM Serretti A A Smit J H JH Stefanis N C NC Surtees P G PG Völzke H H Weinstein M M Whooley M M Nurnberger J I JI Breslau N N Bierut L J LJ

Molecular psychiatry 20170404 1

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses o ...[more]

PMID: 28373689

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Project description:BackgroundDebate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.Methods/designTo improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.Study eligibility criteriaOur goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.Data sourcesThis project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.DiscussionVariation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

Project description:OBJECTIVE: Neurobiological and clinical studies suggest that childhood maltreatment may result in functional and structural nervous system changes that predispose the individual to depression. This vulnerability appears to be modulated by a polymorphism in the serotonin gene-linked promoter region (5-HTTLPR). Little is known, however, about the persistence of this vulnerability across the life span, although clinical studies of adult populations suggest that gene-environment interaction may diminish with aging. METHOD: Depressive symptomatology and adverse and protective childhood events were examined in a population of 942 persons aged 65 years and older, taking into account sociodemographic characteristics and proximal competing causes of depression (widowhood, recent life events, vascular and neurologic disorder, and disability). Subjects were recruited between March 1999 and February 2001 and were diagnosed as depressed if they met 1 of 3 criteria: a diagnosis of major depression on the Mini-International Neuropsychiatric Interview, a score higher than 16 on the Center for Epidemiologic Studies-Depression Scale, or current treatment with an antidepressant. RESULTS: Exposure to traumatic events in childhood doubled the risk of late-life depression and increased the risk of repeated episodes. Not all events were found to be pathogenic; significant risk was associated with excessive sharing of parental problems, poverty or financial difficulties, mental disorder in parents, excessive physical punishment, verbal abuse from parents, humiliation, and mistreatment by an adult outside the family. Interactions were observed between the 5-HTTLPR long (L) allele, poverty, and excessive sharing of parental problems. CONCLUSIONS: Certain types of childhood trauma continue to constitute risk factors for depression in old age, outweighing more proximal causes. Gene environment vulnerability interaction is linked in older age to the L-carrying genotype, modulating the effects of general environmental conditions rather than aggressive acts on the individual, perhaps due to increased cardiac reactivity.

Project description:BackgroundPrevious research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response.ResultsCompared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = -.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040).ConclusionsBoth early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.

Project description:BACKGROUND:Despite the growing consensus that collaborative care is effective, limited research has focused on the importance of collaborative care fidelity as it relates to mental health clinical outcomes. OBJECTIVE:To assess the relationship of collaborative care fidelity on symptom trajectories and clinical outcomes among military service members enrolled in a multi-site randomized controlled trial for the treatment of depression and posttraumatic stress disorder (PTSD). DESIGN:Study data for our analyses came from a two-parallel arm randomized trial that evaluated the effectiveness of a centralized collaborative care model compared to the existing collaborative care model for the treatment of PTSD and depression. All patients were included in the analyses to evaluate how longitudinal trajectories of PTSD and depression scores differed across various collaborative care fidelity groupings. PARTICIPANTS:A total of 666 US Military Service members screening positive for probable PTSD or depression through primary care. MAIN MEASURES:Disease registry data from a web-based clinical management support tool was used to measure collaborative care fidelity for patients enrolled in the trial. Participant depression and PTSD symptoms were collected independently from research survey assessments at four time points across the 1-year trial period. Treatment utilization records were acquired from the Military Health System administrative records to determine mental health service use. KEY RESULTS:Consistent and late fidelity to the collaborative care model predicted an improving symptom trajectory over the course of treatment. This effect was more pronounced for patients with depression than for patients with PTSD. CONCLUSIONS:Long-term fidelity to key collaborative care elements throughout care episodes may improve depression outcomes, particularly for patients with elevated symptoms. More controlled research is needed to further understand the influence of collaborative care fidelity on clinical outcomes. TRIAL REGISTRATION:Clinicaltrials.gov Identifier NCT01492348.

Dataset Information

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

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