Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
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