Open Access Open Badges Study protocol

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression

Robert C Culverhouse12*, Lucy Bowes3, Naomi Breslau4, John I Nurnberger Jr5, Margit Burmeister678, David M Fergusson9, Marcus Munafò10, Nancy L Saccone11, Laura J Bierut12 and On behalf of the 5-HTTLPR, Stress, and Depression Consortium

Author Affiliations

1 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

2 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA

3 Department of Social Policy and Intervention, University of Oxford, Oxford, UK

4 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA

5 Institute of Psychiatric Research, Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

6 Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

7 Department of Human Genetics, University of Michigan, Ann Arbor MI, USA

8 Department of Psychiatry, University of Michigan, Ann Arbor MI, USA

9 Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

10 MRC Integrative Epidemiology Unit, UK Centre for Tobacco Control Studies and School of Experimental Psychology, University of Bristol, Bristol, UK

11 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

12 Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

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BMC Psychiatry 2013, 13:304  doi:10.1186/1471-244X-13-304

Published: 12 November 2013



Debate 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.


To 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 criteria: Our 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 sources: This 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.


Variation 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.