1. 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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Lucy Bowes, Richard Burns, Alex Hatzimanolis, Gonneke Willemsen, Martin A. Kennedy, Kathryn J. Lester, Katerina A.B. Gawronski, Udo Dannlowski, Alison Goate, Carolyn Coffey, Matthias Nauck, David Stacey, Ricardo Araya, Frank Bellivier, Cecilia Åslund, Catherine Toben, Catharine Jawahar, Karen Ritchie, Emilie Olié, Gyorgy Bagdy, Nicholas G. Martin, Robert Culverhouse, Isabelle Jaussent, Peter Petschner, Eric O. Johnson, Nancy L. Saccone, Sandra Villafuerte, Mohamed Lajnef, John I. Nurnberger, Volker Arolt, Laura Mandelli, Philippe Courtet, Henry Völzke, Yinjiao Ma, Craig A. Olsson, Y. Tian, Bernhard T. Baune, Keriann Little, Wouter J. Peyrot, Nicholas W.J. Wainwright, Helen L. Fisher, Brenda W.J.H. Penninx, Manfred Laucht, E.J.C. de Geus, Jan Smit, Sébastien Guillaume, J. M. Scheid, S Van der Auwera, Christian Schwahn, Hans-Jörgen Grabe, Kent W. Nilsson, Xenia Gonda, Dana A. Glei, Gabriella Juhasz, Bruno Etain, C. Holzman, Maxine Weinstein, Thalia C. Eley, Kaarin J. Anstey, Marco Sarchiapone, John Francis William Deakin, Naomi Breslau, P. G. Surtees, John Kramer, J-J Hottenga, Enda M. Byrne, Marcus R. Munafò, Christine Jennen-Steinmetz, Laura J. Bierut, Albertine J. Oldehinkel, Noreen Goldman, Dorret I. Boomsma, Simon Easteal, Margit Burmeister, John Horwood, George C Patton, Tobias Banaschewski, David M. Fergusson, Amy C. Horton, Mary A. Whooley, J. C. Wang, Esther Nederhof, H. M. Zu Schwabedissen, Grant C.B. Sinnamon, Christian Otte, Sarah Cohen-Woods, Ian M. Anderson, William L. Coventry, Tracy Air, Christel M. Middeldorp, Nicholas C. Stefanis, Alessandro Serretti, Johan Ormel, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, roussel, pascale, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de psychiatrie adulte, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital La Colombière, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], Hopital Saint-Louis [AP-HP] (AP-HP), Culverhouse, R.C., Saccone, N.L., Horton, A.C., Ma, Y., Anstey, K.J., Banaschewski, T., Burmeister, M., Cohen-Woods, S., Etain, B., Fisher, H.L., Goldman, N., Guillaume, S., Horwood, J., Juhasz, G., Lester, K.J., Mandelli, L., Middeldorp, C.M., Olié, E., Villafuerte, S., Air, T.M., Araya, R., Bowes, L., Burns, R., Byrne, E.M., Coffey, C., Coventry, W.L., Gawronski, K.A.B., Glei, D., Hatzimanolis, A., Hottenga, J.-J., Jaussent, I., Jawahar, C., Jennen-Steinmetz, C., Kramer, J.R., Lajnef, M., Little, K., Zu Schwabedissen, H.M., Nauck, M., Nederhof, E., Petschner, P., Peyrot, W.J., Schwahn, C., Sinnamon, G., Stacey, D., Tian, Y., Toben, C., Van Der Auwera, S., Wainwright, N., Wang, J.-C., Willemsen, G., Anderson, I.M., Arolt, V., Aslund, C., Bagdy, G., Baune, B.T., Bellivier, F., Boomsma, D.I., Courtet, P., Dannlowski, U., De Geus, E.J.C., Deakin, J.F.W., Easteal, S., Eley, T., Fergusson, D.M., Goate, A.M., Gonda, X., Grabe, H.J., Holzman, C., Johnson, E.O., Kennedy, M., Laucht, M., Martin, N.G., Munafò, M.R., Nilsson, K.W., Oldehinkel, A.J., Olsson, C.A., Ormel, J., Otte, C., Patton, G.C., Penninx, B.W.J.H., Ritchie, K., Sarchiapone, M., Scheid, J.M., Serretti, A., Smit, J.H., Stefanis, N.C., Surtees, P.G., Völzke, H., Weinstein, M., Whooley, M., Nurnberger, J.I., Breslau, N., Bierut, L.J., Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Etudes des Combustibles (DEC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, China Jiliang University (CJLU), Psychiatry, and APH - Digital Health
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DISORDER ,Netherlands Twin Register (NTR) ,SAMPLE ,[SDV]Life Sciences [q-bio] ,Brain and Behaviour ,0302 clinical medicine ,Cooperative Behavior ,Gene–environment interaction ,Depression (differential diagnoses) ,Serotonin Plasma Membrane Transport Proteins ,RISK ,Depression ,Tobacco and Alcohol ,Interaction hypothesis ,Life Change Event ,Justice and Strong Institutions ,3. Good health ,[SDV] Life Sciences [q-bio] ,ENVIRONMENT INTERACTION ,Psychiatry and Mental health ,Meta-analysis ,Psychology ,Serotonin Plasma Membrane Transport Protein ,Molecular Biology ,Cellular and Molecular Neuroscience ,Psychiatry and Mental Health ,Human ,Clinical psychology ,SDG 16 - Peace ,LIFE EVENTS ,Genotype ,POLYMORPHISM 5-HTTLPR ,Stress ,Article ,CHILDHOOD MALTREATMENT ,Life Change Events ,03 medical and health sciences ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Risk factor ,Depressive Disorder ,SEROTONIN TRANSPORTER GENE ,Stressor ,SDG 16 - Peace, Justice and Strong Institutions ,MAJOR DEPRESSION ,030227 psychiatry ,5-HTTLPR ,Behavioral medicine ,COHORT PROFILE ,Psychological ,Gene-Environment Interaction ,Stress, Psychological ,030217 neurology & neurosurgery - 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.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.
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- 2018
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