Evidence map›Paper›PMID 28373689›Full record

SynthesisMolecular psychiatry2018

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, N L Saccone, A C Horton, Y Ma, K J Anstey, T Banaschewski, M Burmeister, S Cohen-Woods, B Etain, H L Fisher and 83 more

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Molecular psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 137 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
137citing papers in PubMed, 9 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

137 citing papers in PubMed, 9 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Pooled it
  6. Pooled it
  7. Imaging genetics paradigms in depression research: Systematic review and meta-analysis.Progress in neuro-psychopharmacology & biological psychiatry · 2018
    Pooled it
  8. Pooled it
  9. Pooled it
  10. Trial
  11. Trial
  12. Trial
  13. Article
  14. Article
  15. Article
  16. Article
  17. Review
  18. Review
  19. Article
  20. Article

77 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

93 authors.

R C CulverhouseDepartment of Medicine and Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
N L SacconeDepartment of Genetics and Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
A C HortonDepartment of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Y MaDepartment of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
K J AnsteyCentre for Research on Ageing, Health and Wellbeing, The Australian National University, Canberra, ACT, Australia.
T BanaschewskiDepartment of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
M BurmeisterDepartment of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
S Cohen-WoodsSchool of Psychology, Faculty of Social and Behavioural Sciences, Flinders University, Adelaide, SA, Australia.
B EtainSorbonne Paris Cité, Université Paris Diderot, UMR-S 1144, Paris, France.ORCID 0000-0002-5377-1488
H L FisherSocial, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
N GoldmanOffice of Population Research, Princeton University, Princeton, NJ, USA.
S GuillaumeUniversité Montpellier, Montpellier, France.ORCID 0000-0002-6769-9982
J HorwoodDepartment of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand.
G JuhaszMTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.ORCID 0000-0002-5975-4267
K J LesterSchool of Psychology, University of Sussex, Brighton, UK.
L MandelliDepartment of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
C M MiddeldorpDepartment of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
E OliéUniversité Montpellier, Montpellier, France.
S VillafuerteDepartment of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
T M AirDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
R ArayaCentre for Global Mental Health, London School of Hygiene and Tropical Medicine, London, UK.
L BowesDepartment of Experimental Psychology, University of Oxford, Oxford, UK.
R BurnsCentre for Research on Ageing, Health and Wellbeing, The Australian National University, Canberra, ACT, Australia.
E M ByrneInstitute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
C CoffeyCentre for Adolescent Health, Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
W L CoventryDiscipline of Psychology, University of New England, Armidale, NSW, Australia.
K A B GawronskiDepartment of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
D GleiCenter for Population and Health, Georgetown University, Washington, DC, USA.
A HatzimanolisDepartment of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
J-J HottengaDepartment of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
I JaussentINSERM U1061 Neuropsychiatry, Montpellier, France.
C JawaharDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
C Jennen-SteinmetzDepartment of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
J R KramerDepartment of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
M LajnefINSERM U955, Creteil, France.
K LittleMurdoch Childrens Research Institute, Melbourne, VIC, Australia.
H M Zu SchwabedissenBiopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
M NauckInstitute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
E NederhofUniversity of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
P PetschnerDepartment of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
W J PeyrotDepartment of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, The Netherlands.
C SchwahnDepartment of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany.
G SinnamonDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
D StaceyDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
Y TianDepartment of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
C TobenDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
S Van der AuweraDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
N WainwrightDepartment of Public Health and Primary Care, School of Clinical Medicine, Cambridge, UK.
J-C WangDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
G WillemsenDepartment of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
I M AndersonNeuroscience and Psychiatry Unit, The University of Manchester, Manchester, UK.
V AroltDepartment of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
C ÅslundCentre for Clinical Research, Uppsala University, Uppsala, Sweden.
G BagdyDepartment of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
B T BauneDiscipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
F BellivierSorbonne Paris Cité, Université Paris Diderot, UMR-S 1144, Paris, France.
D I BoomsmaDepartment of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
P CourtetUniversité Montpellier, Montpellier, France.
U DannlowskiDepartment of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
E J C de GeusDepartment of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
J F W DeakinNeuroscience and Psychiatry Unit, The University of Manchester, Manchester, UK.
S EastealJohn Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
T EleyKing's College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
D M FergussonDepartment of Psychological Medicine, University of Otago Christchurch, Christchurch, New Zealand.
A M GoateDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
X GondaDepartment of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
H J GrabeDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
C HolzmanDepartment of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
E O JohnsonFellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
M KennedyDepartment of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
M LauchtDepartment of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
N G MartinGenetic Epidemiology, QIMR Berghofer, Brisbane, QLD, Australia.
M R MunafòMRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
K W NilssonCentre for Clinical Research, Uppsala University, Uppsala, Sweden.
A J OldehinkelUniversity of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
C A OlssonDeakin University Geelong, Centre for Social and Early Emotional Development, School of Psychology, Faculty of Health, Burwood, VIC, Australia.
J OrmelUniversity of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, The Netherlands.
C OtteCharité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie Campus Benjamin Franklin, Berlin, Germany.
G C PattonDepartment of Paediatrics, Murdoch Childrens Research Institute, University of Melbourne, Melbourne, VIC, Australia.
B W J H PenninxDepartment of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, The Netherlands.
K RitchieINSERM U1061 Neuropsychiatry, Montpellier, France.
M SarchiaponeDepartment of Health Sciences, University of Molise, Campobasso, Italy.
J M ScheidDepartment of Psychiatry, Michigan State University, East Lansing, MI, USA.
A SerrettiDepartment of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
J H SmitDepartment of Psychiatry, VU University Medical Center & GGZ inGeest, Amsterdam, The Netherlands.
N C StefanisDepartment of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
P G SurteesDepartment of Public Health and Primary Care, School of Clinical Medicine, Cambridge, UK.
H VölzkeInstitute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
M WeinsteinCenter for Population and Health, Georgetown University, Washington, DC, USA.
M WhooleyVeterans Affairs Health Care System and University of California, San Francisco, CA, USA.
J I NurnbergerInstitute of Psychiatric Research, Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
N BreslauDepartment of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
L J BierutDepartment of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.

Funding

NIMH Center Repository Supporting Stem Cell ResearchU24MH068457 · NIMH · RUTGERS THE ST UNIV OF NJ NEW BRUNSWICK · PI BRZUSTOWICZ, LINDA M, KNOWLES, JAMES A · 2003 to 2024
$213.8M
Subject CollectionU10AA008401 · NIAAA · SUNY DOWNSTATE MEDICAL CENTER · PI ARPANA AGRAWAL, VICTOR M HESSELBROCK · 1989 to 2026
$162.7M
VESICULAR LOCALIZATION AND FUNCTION OF PRESENILIN 1 FRAGMENTP50AG005138 · NIA · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI GROSSMAN, HILLEL · 1985 to 2019
$37.9M
Research Education ComponentP30AG066514 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI NIKOLAOS K ROBAKIS · 2020 to 2026
$31.0M
The Collaborative Genetic Study of Nicotine DependenceP01CA089392 · NCI · WASHINGTON UNIVERSITY · PI GOATE, ALISON M · 2001 to 2012
$17.3M
Family Study of Risk for Alcoholism Over the Life CourseR37AA007065 · NIAAA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ZUCKER, ROBERT ALPERT · 2003 to 2012
$10.6M
BIODEMOGRAPHY OF HEALTH, SOCIAL FACTORS &LIFE CHALLENGER01AG016661 · NIA · RAND CORPORATION · PI WEINSTEIN, MAXINE A · 1999 to 2013
$9.5M
Infrastructure for Population Research at PrincetonR24HD047879 · NICHD · PRINCETON UNIVERSITY · PI MASSEY, DOUGLAS S · 2004 to 2013
$7.3M
Integration of Genomics & Transcriptomics in Normal Twins & Major DepressionRC2MH089951 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SULLIVAN, PATRICK F · 2009 to 2010
$6.5M
RISK AND COPING IN CHILDREN OF ALCOHOLICSR01AA007065 · NIAAA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HEITZEG, MARY M · 1987 to 2017
$6.1M
BIODEMOGRAPHY OF HEALTH, SOCIAL FACTORS AND LIFE CHANGER01AG016790 · NIA · PRINCETON UNIVERSITY · PI GOLDMAN, NOREEN · 1999 to 2014
$5.6M
Etiologic Heterogeneity in Preterm DeliveryR01HD034543 · NICHD · MICHIGAN STATE UNIVERSITY · PI HOLZMAN, CLAUDIA B. · 1997 to 2005
$5.3M
British Heart FoundationCancer Research UK C865/A2883Department of HealthMedical Research Council G0300128Medical Research Council G0701420Medical Research Council G1002366Medical Research Council G120/635Medical Research Council G9502233Medical Research Council G9815508Medical Research Council G9901258Medical Research Council MC_PC_15018Medical Research Council MC_UU_00011/7Medical Research Council MC_UU_12013/6Medical Research Council MR/M011372/1NCCDPHP CDC HHS U01 DP000143NCI NIH HHS P01 CA089392NHLBI NIH HHS R01 HL079235NIAAA NIH HHS R01 AA007065NIAAA NIH HHS R01 AA007535NIAAA NIH HHS R01 AA007728NIAAA NIH HHS R01 AA010249NIAAA NIH HHS R37 AA007065NIAAA NIH HHS R37 AA007728NIAAA NIH HHS U10 AA008401NIA NIH HHS P30 AG066514NIA NIH HHS P50 AG005138NIA NIH HHS R01 AG016661NIA NIH HHS R01 AG016790NICHD NIH HHS P2C HD047879NICHD NIH HHS R01 HD034543NICHD NIH HHS R01 HD042157NICHD NIH HHS R24 HD047879NIDA NIH HHS K99 DA023549NIDA NIH HHS R01 DA026911NIDA NIH HHS R01 DA036583NIDA NIH HHS R21 DA033827NIMH NIH HHS R01 MH081802NIMH NIH HHS RC2 MH089951NIMH NIH HHS RC2 MH089995NIMH NIH HHS U24 MH068457Wellcome TrustWellcome Trust 102215/2/13/2
6 · The paper itself

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.

Indexed as

Cooperative BehaviorDepressionGene-Environment InteractionGenetic Predisposition to DiseaseGenotypeHumansLife Change EventsSerotonin Plasma Membrane Transport ProteinsStress, PsychologicalSerotonin Plasma Membrane Transport ProteinsSLC6A4 protein, human

Identifiers

PMID28373689
PMCPMC5628077

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.