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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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Molecular psychiatry

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      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      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 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed 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members or self-identified in response to our protocol (published prior to the start of analysis 1 ) with qualifying unpublished data were also invited to participate.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 generalizable, but must be of modest effect size and only observable in limited situations.

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      Most cited references 73

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      Power failure: why small sample size undermines the reliability of neuroscience.

      A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.
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        Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.

        In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
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          PSYCHOLOGY. Estimating the reproducibility of psychological science.

          Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
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            Author and article information

            Affiliations
            [1 ]Department of Medicine and Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
            [2 ]Department of Genetics and Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
            [3 ]Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
            [4 ]Centre for Research on Ageing, Health and Wellbeing, The Australian National University, Canberra, Australia
            [5 ]Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany
            [6 ]Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
            [7 ]Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
            [8 ]Discipline of Psychiatry, Flinders University, Adelaide, Australia
            [9 ]Sorbonne Paris Cité, Université Paris Diderot, UMR-S 1144, Paris, France
            [10 ]AP-HP, Groupe Saint-Louis-Lariboisière-F. Widal, Paris, France
            [11 ]INSERM, U1144, Paris, France
            [12 ]Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
            [13 ]Office of Population Research, Princeton University, Princeton, NJ, USA
            [14 ]Université Montpellier; Montpellier, France
            [15 ]INSERM U1061 Neuropsychiatry, Montpellier, France
            [16 ]Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
            [17 ]Department of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand
            [18 ]MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
            [19 ]Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
            [20 ]Neuroscience and Psychiatry Unit, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
            [21 ]School of Psychology, University of Sussex, Brighton, UK
            [22 ]Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
            [23 ]Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
            [24 ]Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
            [25 ]Discipline of Psychiatry, University of Adelaide, Adelaide, Australia
            [26 ]Centre for Global Mental Health, London School of Hygiene and Tropical Medicine, London, UK
            [27 ]Department of Experimental Psychology, University of Oxford, Oxford, UK
            [28 ]Queensland Brain Institute, University of Queensland, Brisbane, Australia
            [29 ]Centre for Adolescent Health, Murdoch Childrens Research Institute, Melbourne, Australia
            [30 ]Discipline of Psychology, University of New England, Adelaide, Australia
            [31 ]Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
            [32 ]Center for Population and Health, Georgetown University, Washington, DC, USA
            [33 ]University Mental Health Research Institute and Department of Psychiatry, University of Athens School of Medicine, Athens, Greece
            [34 ]EMGO+ institute for Health and Care Research, VU Medical Center Amsterdam, Amsterdam, the Netherlands
            [35 ]Department of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany
            [36 ]Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
            [37 ]INSERM U955, Creteil, France
            [38 ]Murdoch Childrens Research Institute, Melbourne, Australia
            [39 ]Department of Paediatrics and School of Psychological Sciences, University of Melbourne, Melbourne, Australia
            [40 ]Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
            [41 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
            [42 ]University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, the Netherlands
            [43 ]MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
            [44 ]Department of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, the Netherlands
            [45 ]Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany
            [46 ]Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA
            [47 ]Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
            [48 ]Department of Public Health and Primary Care, School of Clinical Medicine, Cambridge, UK
            [49 ]Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
            [50 ]Manchester Academic Health Sciences Centre, Manchester, UK
            [51 ]Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany
            [52 ]Centre for Clinical Research, Uppsala University, Uppsala, Sweden
            [53 ]Västmanland County Hospital Västerås, Västerås, Sweden
            [54 ]Department of Psychiatry, University of Marburg, Marburg, Germany
            [55 ]John Curtin School of Medical Research, The Australian National University, Canberra, Australia
            [56 ]King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK
            [57 ]Department of Psychiatry and Psychotherapy, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary
            [58 ]Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA
            [59 ]Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
            [60 ]Genetic Epidemiology, QIMR Berghofer, Brisbane, Australia
            [61 ]MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
            [62 ]UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK
            [63 ]Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Deakin University, Geelong, Australia
            [64 ]Centre for Adolescent Health, Murdoch Childrens Research Institute, Melbourne, Australia
            [65 ]Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie Campus Benjamin Franklin, Berlin, Germany
            [66 ]Department of Paediatrics, Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Australia
            [67 ]Department of Health Sciences, University of Molise, Campobasso, Italy
            [68 ]Department of Psychiatry, Michigan State University, East Lansing, MI, USA
            [69 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
            [70 ]Veterans Affairs Health Care System and University of California, San Francisco, CA, USA
            [71 ]Institute of Psychiatric Research, Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
            Journal
            9607835
            20545
            Mol Psychiatry
            Mol. Psychiatry
            Molecular psychiatry
            1359-4184
            1476-5578
            15 April 2017
            04 April 2017
            05 October 2017
            28373689 5628077 10.1038/mp.2017.44 NIHMS849357

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            Molecular medicine

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