Joint grant from the United Kingdom Medical Research Council and GlaxoSmithKline (Grant No. G0701420) and the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London. This work presents independent research in part funded by the NIHR. Also supported by the Wellcome Trust Grant No. 086635 (JJHR); NIHR Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London (SCW); a Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme (MRiv); European Commission Grant Agreement No. 115008 (RU, PM); and Canada Research Chairs program (http://www. chairs-chaires.gc.ca/) (RU). Dr. Aitchison holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the government of Alberta, Canada. The Genome Based Therapeutic Drugs for Depression study was funded by a European Commission Framework 6 grant, European Commission Contract Reference LSHB-CT-2003-503428, and GlaxoSmithKline. Genotyping was performed at the Centre Nationale De Genotypage, Evry, Paris. We acknowledge the contribution of phase 2 of the Wellcome Trust Case Control Consortium in providing access to control datasets from the 1958 British birth cohort and the National Blood Service cohort.
The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-2001-01254); the European Community's Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King's College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT-2003-503428). Genotyping of STAR*D was supported by NIMH Grant No. MH072802 (to SPH). STAR*D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT-2001-01254, QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [to UD]), Innovative Medizinische Forschung of the Medical Faculty of Mu¨nster (Grant Nos. DA120903, DA111107, and DA211012 [all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006). Supplementary material cited in this article is available online at http:// dx.doi.org/10.1016/j.biopsych.2016.05.010. ; Peer reviewed ; Publisher PDF
PUBLISHED ; BACKGROUND: Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue. AIMS: To investigate whether higher BMI increases the risk of major depression. METHOD: Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI. RESULTS: Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient -0.03, 95% CI -0.18 to 0.13, P = 0.73; GRS: coefficient -0.02, 95% CI -0.11 to 0.07, P = 0.62). CONCLUSIONS: Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding ; This study was funded by the UK Medical Research Council and GlaxoSmithKline (G0701420). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair funded by the Government of Alberta. O.S.P.D. was supported by a Sir Henry Wellcome Fellowship from the Wellcome Trust (WT088984). This work was funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King?s College London. This article/paper/report presents independent research in part funded by the NIHR. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health.
The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www. geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10-002, 904-61-193, 480-04004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-200101254); the European Community's Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. r G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King's College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT2003- 503428). Genotyping of STAR* D was supported by NIMH Grant No. MH072802 (to SPH). STAR* D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT2001-01254,QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [ to UD]), Innovative Medizinische Forschung of the Medical Faculty of Munster (Grant Nos. DA120903, DA111107, and DA211012 [ all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006).r The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant No. U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control dataset were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression.r We acknowledge the contributions of Dr. George S Zubenko and Dr. Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. We are grateful to Knowledge Networks (Menlo Park, CA) for assistance in collecting the control dataset. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. We thank V. Mooser, G. Weaber, and P. Vollenweider who initiated the CoLaus project. We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We would like to acknowledge the PRISME-study group, Denmark, for collection of the PRISME samples. We thank David M. Hougaard, Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark; Preben Bo Mortensen, National Centre for Register-based Research, Aarhus University, Denmark; Merete Nordentoft, Mental Health Centre, Copenhagen, Denmark; and The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark. Funding from the BBSRC and MRC is gratefully acknowledged.r Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report.r SS, HS, KS, and TET are employees of deCODE Genetics/Amgen. VA received funds from the German Federal Ministry of Education and Research, from the European Union (FP 7), and from the Interdisciplinary Center for Clinical Research Munster, and he has served on the advisory boards of, or has given presentations on behalf of the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, Otsuka, and Trommsdorff. BTB has received funding from the National Health and Medical Research Council Australia and honoraria from Lundbeck, BristolMeyers Squibb, Sanofi, Servier, Astra-Zeneca, Pfizer. IJD is supported by the MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Grant No. MR/K026992/1). HJG has received funding from German Research Foundation and Federal Ministry of Education and Research Germany and speakers honoraria from Eli Lilly and Servier. CH acknowledges support from the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). DJM is supported by an , funded by the Chief Scientist Office. AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation and has received research support from Pfizer, Janssen, and Lilly. CMM was supported by the Netherlands Organization for Scientific Research (Grant No. NOW VENI 916-76-125). BM- M has consulted for Affectis Pharmaceuticals. MP has served on the advisory boards of Lundbeck and Eli Lilly ; BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (.27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p 5 5.2 3 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder. ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH085520 MH080403 ; SURFsara ; Netherlands Scientific Organization NWO 480-05-003 ; Department of Psychology, Vrije Universiteit Amsterdam ; Dutch Brain Foundation ; Federal Ministry of Education & Research (BMBF) 01GS08144 01GS08147 ; National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders ; e:Med Programme 01ZX1314A 01ZX1314G ; German Research Foundation (DFG) FOR2107 RI908/11-1 NO246/10-1 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH061686 MH059542 MH075131 MH059552 MH059541 MH060912 ; Federal Ministry of Education & Research (BMBF) 01ES0811 ; Bavarian Ministry of Commerce ; Federal Ministry of Education & Research (BMBF) NGFN2 NGFN-Plus FKZ 01GS0481 01GS08145 ; Netherlands Organization for Scientific Research (MagW/ZonMW) 904-61-090 985-10-002 904-61-193 480-04004 400-05-717 912-100-20 ; Spinozapremie 56-464-14192 ; Geestkracht program 10-000-1002 ; Center for Medical Systems Biology (NWO Genomics) ; Biobanking and Biomolecular Resources Research Infrastructure ; Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam ; BIC/BioAssist/RK 2008.024 ; European Science Foundation (ESF) EU/QLRT-200101254 ; European Union (EU) FP7/2007-2013 ; ENGAGE HEALTH-F4-2007-201413 ; European Science Council ERC 230374 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA ; GAIN ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) MH081802 MH072802 N01MH90003 ; National Health and Medical Research Council of Australia 241944 339462 389927 389875 389891 389892 389938 442915 442981 496675 496739 552485 552498 613602 613608 613674 619667 ; Australian Research Council FT0991360 FT0991022 ; FP-5 GenomEUtwin Project QLG2-CT-2002-01254 ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA AA07535 AA10248 AA13320 AA13321 AA13326 AA14041 MH66206 DA12854 DA019951 U01 DK066134 ; Center for Inherited Disease Research (Baltimore, MD) ; UK Medical Research Council and GlaxoSmithKline G0701420 ; National Institute for Health Research (NIHR) ; Maudsley National Health Service Foundation Trust ; Institute of Psychiatry, King's College London ; Medical Research Council UK (MRC) G0000647 ; European Union (EU) 286213 ; European Commission Framework 6 grant (EC) LSHB-CT2003- 503428 ; GlaxoSmithKline ; Faculty of Biology and Medicine of Lausanne ; Swiss National Science Foundation (SNSF) 3200B0-105993 3200B0-118308 33CSCO-122661 33CS30-139468 33CS30-148401 ; GlaxoSmithKline Clinical Genetics ; Federal Ministry of Education & Research (BMBF) 01ZZ9603 01ZZ0103 01ZZ0403 03ZIK012 ; Ministry of Cultural Affairs ; Social Ministry of the Federal State of Mecklenburg-West Pomerania ; Siemens Healthcare, Erlangen, Germany ; German Research Foundation (DFG) GR 1912/5-1 FOR 2107 DA1151/5-1 ; Swedish Ministry for Higher Education ; Swedish Research Council M-2005-1112 ; GenomEUtwin QLG2-CT-2002-01254 EU/QLRT2001-01254 ; Swedish Foundation for Strategic Research ; Danske Strategiske Forskningsrad (DSF) ; Stanley Research Foundation ; European Union (EU) N Health-F2-2008-222963 ; Innovative Medizinische Forschung of the Medical Faculty of Munster DA120903 DA111107 DA211012 ; Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" 104036/Z/14/Z ; Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 ; Scottish Funding Council HR03006 ; Broad Institute Center for Genotyping and Analysis U54 RR020278 ; NARSAD ; Biotechnology and Biological Sciences Research Council (BBSRC) ; Medical Research Council UK (MRC) ; Federal Ministry of Education & Research (BMBF) ; Interdisciplinary Center for Clinical Research Munster ; National Health and Medical Research Council of Australia ; MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative MR/K026992/1 ; German Research Foundation (DFG) ; Federal Ministry of Education ; Research Germany and speakers honoraria from Eli Lilly and Servier ; Medical Research Council UK (MRC) ; Biotechnology and Biological Sciences Research Council (BBSRC) ; NRS Career Fellowship - Chief Scientist Office ; Scottish Funding Council Senior Clinical Fellowship ; Dame Theresa and Mortimer Sackler Foundation ; Netherlands Organization for Scientific Research (NWO) NOW VENI 916-76-125 ; Lundbeckfonden R155-2014-1724 ; Medical Research Council UK (MRC) MR/K026992/1 MC_PC_U127561128 1292844 ; Chief Scientist Office CZD/16/6/4
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. ; ALSPAC: Grant 102215/2/13/2 from The Wellcome Trust and grant MC_UU_12013- /6 from the UK Medical Research Council. The University of Bristol also provides core support for ALSPAC. LB receives funding as an Early Career Research Fellow from the Leverhulme Trust. MRM is a member of the UK Centre for Tobacco and Alcohol Studies, a UK Clinical Research Council Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. ASPIS: EKBAN 97 from the General Secretariat of Research and Technology, Greek Ministry of Development. ATP: Grants DP130101459, DP160103160 and APP1082406 from the Australian Research Council and The National Health and Medical Research Council of Australia. CHDS: Grant HRC 11/792 from the Health Research Council of New Zealand. CoFaMS: Grant APP1060524 to BTB from the National Health and Medical Research Council of Australia. We acknowledge the University of Adelaide for the provision of seed funding in support of this project. COGA: Grant U10AA008401 from the National Institutes of Health, NIAAA and NIDA. COGEND: National Institutes of Health grants P01CA089392 from NCI and R01DA036583 from NIDA. DeCC: Grant G0701420 from the UK Medical Research Council, and a UK MRC Population Health Scientist fellowship (G1002366) and an MQ Fellows Award (MQ14F40) to Helen L Fisher. EPIC-Norfolk: Grants G9502233, G0300128, C865/A2883 from the UK Medical Research Council and Cancer Research UK. ESPRIT Montpellier: An unconditional grant from Novartis and from the National Research Agency (ANR Project 07 LVIE004). G1219: A project grant from the WT Grant Foundation and G120/635, a Career Development Award from the UK Medical Research Council to Thalia Eley. The GENESiS project was supported by Grant G9901258 from the UK Medical Research Council. This study presents independent research part- funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. GAN12-France: Research Protocol C0829 from INSERM; Research Protocol GAN12 from Assistance Publique des Hôpitaux de Paris; ANR-11-IDEX- 0004 from Investissements d'Avenir program managed by the ANR, and RTRS Sante Mentale from Fondation FondaMental. GENESIS: Grant PHRC UF 7653 & ANR NEURO 2007 'GENESIS' from CHU Montpellier & Agence Nationale de la Recherche. Heart and Soul: Epidemiology Merit Review Program from the Department of Veterans Affairs; National Institutes of Health grant R01HL-079235 from NHLBI; Generalist Physician Faculty Scholars Program from the Robert Woods Johnson foundation; Paul Beeson Faculty Scholars Program from the American Federation for Aging Research; and a Young Investigator Award from the Bran and Behavior Research Foundation. MARS: Grant LA 733/2-1 from German Research Foundation (DFG) and the Federal Ministry for Education and Research as part of the 'National Genome Research Network'. MLS: National Institutes of Health grants R01 AA07065 and R37 AA07065 from NIAAA. MoodInFlame: Grant EU-FP7- HEALTH-F2-2008-222963 from the European Union. Muenster Neuroimaging Study: Grant FOR2107, DA1151/5-1 from the German Research Foundation (DFG). NEWMOOD: Grants LSHM-CT-2004-503474 from Sixth Framework Program of the European Union; KTIA_NAP_13-1-2013-0001, KTIA_13_NAP-A-II/14 from National Development Agency Hungarian Brain Research Program; KTIA_NAP_13-2-2015-0001 from MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University; support from Hungarian Academy of Sciences, MTA-SE Neuropsychopharmacology and Neurochemistry Research Group; and support from the National Institute for Health Research Manchester Biomedical Research Centre. NESDA/NTR: The Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants Middelgroot-911-09-032, Spinozapremie 56-464- 14192, Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMW 10-000-1002), Center for Medical Systems Biology (CSMB, NWO Genomics), Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMW 912-10-020), NBIC/BioAssist/RK (2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL, 184.021.007), VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Council (ERC Advanced, 230374). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). PATH: Program Grant Number 179805 from the National Health and Medical Research Council of Australia. POUCH: Grants 20FY01-38 and 20-FY04-37 of the Perinatal Epidemiologic Research Initiative Program Grant from the March of Dimes Foundation; National Institutes of Health grant R01 HD34543 from NICHD and NINR; grant 02816-7 from the Thrasher Research Foundation; and grant U01 DP000143-01 from the Centers for Disease Control and Prevention. QIMRtwin: Grants 941177, 971232, 339450, 443011 from the National Health and Medical Research Council of Australia; AA07535, AA07728, AA10249 from US Public Health Service; National Institutes of Health grant K99DA023549-01A2 from NIDA. Additional support was provided by Beyond Blue. SALVe 2001 and SALVe 2006: Grants FO2012-0326, FO2013-0023, FO2014-0243 from The Brain Foundation (Hjärnfonden); SLS-559921 from Söderström-Königska Foundation; 2015-00897 from Swedish Council for Working Life and Social Research; and M15-0239 from Åke Wiberg's Foundation. Additional funding was provided by Systembolagets Råd för Alkoholforskning, SRA and Svenska Spel Research Council. SEBAS: National Institutes of Health grants R01 AG16790, R01 AG16661 and R56 AG01661 from NIA and grant P2CHD047879 from NICHD; and additional financial support from the Graduate School of Arts and Sciences at Georgetown University. SHIP/TREND: This work was supported by the German Federal Ministry of Education and Research within the framework of the e:Med research and funding concept (Integrament) Grant No. 01ZX1314E. Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research Grant Nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403; the Ministry of Cultural Affairs; and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data were supported by the Federal Ministry of Education and Research Grant No. 03ZIK012 and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The Greifswald Approach to Individualised Medicine (GANI_MED) was funded by the Federal Ministry of Education and Research Grant No. 03IS2061A and the German Research Foundation Grant No. GR 1912/5-1. TRAILS: Grants GB-MW 940- 38-011, ZonMW Brainpower 100-001-004, Investment grant 175.010.2003.005, GBMaGW 480-07-001 and Longitudinal Survey and Panel Funding 481-08-013 from the Netherlands Organization for Scientific Research (NWO). Additional funding was provided by the Dutch Ministry of Justice, the European Science Foundation, BBMRINL and the participating centres (UMCG, RUG, Erasmus MC, UU, Radboud MC, Parnassia Bavo group): VAHCS: Grants APP1063091, 1008271 and 1019887 from Australia's National Health and Medical Research Council of Australia (NHMRC).
