Meta-Analysis

. 2018 Jan;23(1):133-142.

doi: 10.1038/mp.2017.44. Epub 2017 Apr 4.

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

R C Culverhouse¹, N L Saccone², A C Horton³, Y Ma³, K J Anstey⁴, T Banaschewski⁵, M Burmeister^{6

7}, S Cohen-Woods⁸, B Etain^{9

10

11}, H L Fisher¹², N Goldman¹³, S Guillaume^{14

15

16}, J Horwood¹⁷, G Juhasz^{18

19

20

21}, K J Lester²², L Mandelli²³, C M Middeldorp^{24

25}, E Olié^{14

15

16}, S Villafuerte⁶, T M Air²⁶, R Araya²⁷, L Bowes²⁸, R Burns⁴, E M Byrne²⁹, C Coffey³⁰, W L Coventry³¹, K A B Gawronski³², D Glei³³, A Hatzimanolis^{34

35}, J-J Hottenga^{24

36}, I Jaussent¹⁵, C Jawahar²⁶, C Jennen-Steinmetz³⁷, J R Kramer³⁸, M Lajnef³⁹, K Little^{40

41}, H M Zu Schwabedissen⁴², M Nauck⁴³, E Nederhof⁴⁴, P Petschner^{19

21

45}, W J Peyrot⁴⁶, C Schwahn⁴⁷, G Sinnamon²⁶, D Stacey²⁶, Y Tian⁴⁸, C Toben²⁶, S Van der Auwera⁴⁹, N Wainwright⁵⁰, J-C Wang⁵¹, G Willemsen^{24

36}, I M Anderson^{20

52}, V Arolt⁵³, C Åslund^{54

55}, G Bagdy^{19

21

45}, B T Baune²⁶, F Bellivier^{9

10

11}, D I Boomsma^{24

25

36}, P Courtet^{14

15

16}, U Dannlowski⁵³, E J C de Geus^{24

36}, J F W Deakin^{20

52}, S Easteal⁵⁶, T Eley⁵⁷, D M Fergusson¹⁷, A M Goate⁵¹, X Gonda^{19

21

45

58}, H J Grabe⁴⁹, C Holzman⁴⁸, E O Johnson⁵⁹, M Kennedy⁶⁰, M Laucht⁵, N G Martin⁶¹, M R Munafò^{62

63}, K W Nilsson^{54

55}, A J Oldehinkel⁴⁴, C A Olsson^{64

41

30}, J Ormel⁴⁴, C Otte⁶⁵, G C Patton⁶⁶, B W J H Penninx⁴⁶, K Ritchie¹⁵, M Sarchiapone⁶⁷, J M Scheid⁶⁸, A Serretti²³, J H Smit⁴⁶, N C Stefanis^{34

35}, P G Surtees⁵⁰, H Völzke⁶⁹, M Weinstein³³, M Whooley⁷⁰, J I Nurnberger Jr⁷¹, N Breslau⁴⁸, L J Bierut³

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, ACT, 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 School of Psychology, Faculty of Social and Behavioural Sciences, Flinders University, Adelaide, SA, 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, Semmelweis University, Budapest, Hungary.
²⁰ Neuroscience and Psychiatry Unit, The University of Manchester, Manchester, UK.
²¹ NAP-A-SE New Antidepressant Target Research Group, Semmelweis University, Budapest, Hungary.
²² School of Psychology, University of Sussex, Brighton, UK.
²³ Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
²⁴ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁵ Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁶ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
²⁷ Centre for Global Mental Health, London School of Hygiene and Tropical Medicine, London, UK.
²⁸ Department of Experimental Psychology, University of Oxford, Oxford, UK.
²⁹ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
³⁰ Centre for Adolescent Health, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
³¹ Discipline of Psychology, University of New England, Armidale, NSW, Australia.
³² Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Center for Population and Health, Georgetown University, Washington, DC, USA.
³⁴ Department of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
³⁵ Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
³⁶ EMGO+ Institute for Health and Care Research, VU Medical Center Amsterdam, Amsterdam, The Netherlands.
³⁷ Department of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
³⁸ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
³⁹ INSERM U955, Creteil, France.
⁴⁰ Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
⁴¹ Department of Paediatrics and School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁴² Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
⁴³ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁴ University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
⁴⁵ MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
⁴⁶ Department of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, The Netherlands.
⁴⁷ Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
⁴⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁵⁰ Department of Public Health and Primary Care, School of Clinical Medicine, Cambridge, UK.
⁵¹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵² Manchester Academic Health Sciences Centre, Manchester, UK.
⁵³ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
⁵⁴ Centre for Clinical Research, Uppsala University, Uppsala, Sweden.
⁵⁵ Västmanland County Hospital Västerås, Västerås, Sweden.
⁵⁶ John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁵⁷ King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
⁵⁸ Department of Psychiatry and Psychotherapy, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary.
⁵⁹ Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
⁶⁰ Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
⁶¹ Genetic Epidemiology, QIMR Berghofer, Brisbane, QLD, Australia.
⁶² MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
⁶³ UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
⁶⁴ Deakin University Geelong, Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Burwood, VIC, 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, VIC, 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.

PMID: 28373689
PMCID: PMC5628077
DOI: 10.1038/mp.2017.44

Meta-Analysis

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

R C Culverhouse et al. Mol Psychiatry. 2018 Jan.

. 2018 Jan;23(1):133-142.

doi: 10.1038/mp.2017.44. Epub 2017 Apr 4.

Authors

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, ACT, 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 School of Psychology, Faculty of Social and Behavioural Sciences, Flinders University, Adelaide, SA, 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, Semmelweis University, Budapest, Hungary.
²⁰ Neuroscience and Psychiatry Unit, The University of Manchester, Manchester, UK.
²¹ NAP-A-SE New Antidepressant Target Research Group, Semmelweis University, Budapest, Hungary.
²² School of Psychology, University of Sussex, Brighton, UK.
²³ Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
²⁴ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁵ Neuroscience Campus Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁶ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
²⁷ Centre for Global Mental Health, London School of Hygiene and Tropical Medicine, London, UK.
²⁸ Department of Experimental Psychology, University of Oxford, Oxford, UK.
²⁹ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
³⁰ Centre for Adolescent Health, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
³¹ Discipline of Psychology, University of New England, Armidale, NSW, Australia.
³² Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Center for Population and Health, Georgetown University, Washington, DC, USA.
³⁴ Department of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
³⁵ Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
³⁶ EMGO+ Institute for Health and Care Research, VU Medical Center Amsterdam, Amsterdam, The Netherlands.
³⁷ Department of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
³⁸ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
³⁹ INSERM U955, Creteil, France.
⁴⁰ Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
⁴¹ Department of Paediatrics and School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁴² Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
⁴³ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁴ University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
⁴⁵ MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
⁴⁶ Department of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, The Netherlands.
⁴⁷ Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
⁴⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁵⁰ Department of Public Health and Primary Care, School of Clinical Medicine, Cambridge, UK.
⁵¹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵² Manchester Academic Health Sciences Centre, Manchester, UK.
⁵³ Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
⁵⁴ Centre for Clinical Research, Uppsala University, Uppsala, Sweden.
⁵⁵ Västmanland County Hospital Västerås, Västerås, Sweden.
⁵⁶ John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁵⁷ King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
⁵⁸ Department of Psychiatry and Psychotherapy, Kutvolgyi Clinical Center, Semmelweis University, Budapest, Hungary.
⁵⁹ Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
⁶⁰ Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
⁶¹ Genetic Epidemiology, QIMR Berghofer, Brisbane, QLD, Australia.
⁶² MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
⁶³ UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
⁶⁴ Deakin University Geelong, Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Burwood, VIC, 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, VIC, 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.

PMID: 28373689
PMCID: PMC5628077
DOI: 10.1038/mp.2017.44

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.

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Figures

**Figure 1**
Forest plots for lifetime depression diagnosis in subjects of all ages based on exposure to childhood maltreatment as the stressor $MODEL: depression = β_{0} + β_{1} (age) + β_{2} (sex) + β_{3} (stress) + β_{4} (gene) + β_{5} (gene \times stress)$ Depression = lifetime depression diagnosis (never depressed = 0; ever depressed = 1) Sex (female = 0; male = 1) Stress = childhood maltreatment (not exposed = 0; exposed = 1) Gene (additive coding in number of S alleles for 5-HTTLPR (LL = 0; LS=1; SS=2)) 1a. **Sex:** Being male consistently and significantly protects from a lifetime diagnosis of depression 1b. **Stress:** Exposure to stress consistently and significantly increases lifetime risk for depression 1c. **Gene:** The S allele (coded additively) is not associated with risk of lifetime depression 1d. **Gene x Stress:** Interaction term is not significant and does not suggest a consistent direction of effect across studies. (Hypothesized direction of effect: OR > 1)

See this image and copyright information in PMC

Comment in

5-HTTLPR × stress hypothesis: is the debate over?
Ancelin ML, Ryan J. Ancelin ML, et al. Mol Psychiatry. 2018 Nov;23(11):2116-2117. doi: 10.1038/mp.2017.195. Mol Psychiatry. 2018. PMID: 28924185 Free PMC article. No abstract available.

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous