Journal
BIOLOGICAL PSYCHIATRY
Volume 81, Issue 4, Pages 325-335Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2016.05.010
Keywords
Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic scoring; Stratification
Categories
Funding
- National Institute of Mental Health (NIMH) [MH085520, MH080403]
- SURFsara
- Netherlands Scientific Organization [NWO 480-05-003]
- department of Psychology
- Dutch Brain Foundation
- 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 [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]
- NIMH R01 [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]
- BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]
- Bavarian Ministry of Commerce
- BMBF in the framework of the National Genome Research [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 [EU/QLRT-200101254]
- European Community's Seventh Framework Program [FP7/2007-2013]
- ENGAGE [HEALTH-F4-2007-201413]
- European Science Council [ERC 230374]
- GAIN of the Foundation for the US National Institutes of Health
- GAIN
- NIMH [MH081802, MH072802, N01MH90003]
- Australian National Health and Medical Research Council [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]
- US National Institutes of Health [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 Specialist Biomedical Research Centre for Mental Health at the South London
- Maudsley National Health Service Foundation Trust
- Institute of Psychiatry, King's College London
- UK Medical Research Council [G0000647]
- Marie Curie Industry-Academia Partnership and Pathways [286213]
- European Commission Framework 6 grant (EC) [LSHB-CT2003- 503428]
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne
- Swiss National Science Foundation [3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401]
- GlaxoSmithKline Clinical Genetics
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare, Erlangen, Germany
- 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
- Danish Strategic Research Council
- Stanley Research Foundation
- European Union [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]
- NIMH
- National Alliance for Research on Schizophrenia and Depression
- BBSRC
- MRC
- German Federal Ministry of Education and Research
- European Union (FP 7)
- Interdisciplinary Center for Clinical Research Munster
- National Health and Medical Research Council 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
- Federal Ministry of Education
- Research Germany and speakers honoraria from Eli Lilly and Servier
- Medical Research Council (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 [NOW VENI 916-76-125]
- National Institute of Mental Health (NIMH) [MH085520, MH080403]
- SURFsara
- Netherlands Scientific Organization [NWO 480-05-003]
- department of Psychology
- Dutch Brain Foundation
- 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 [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]
- NIMH R01 [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]
- BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]
- Bavarian Ministry of Commerce
- BMBF in the framework of the National Genome Research [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 [EU/QLRT-200101254]
- European Community's Seventh Framework Program [FP7/2007-2013]
- ENGAGE [HEALTH-F4-2007-201413]
- European Science Council [ERC 230374]
- GAIN of the Foundation for the US National Institutes of Health
- GAIN
- NIMH [MH081802, MH072802, N01MH90003]
- Australian National Health and Medical Research Council [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]
- US National Institutes of Health [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 Specialist Biomedical Research Centre for Mental Health at the South London
- Maudsley National Health Service Foundation Trust
- Institute of Psychiatry, King's College London
- UK Medical Research Council [G0000647]
- Marie Curie Industry-Academia Partnership and Pathways [286213]
- European Commission Framework 6 grant (EC) [LSHB-CT2003- 503428]
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne
- Swiss National Science Foundation [3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401]
- GlaxoSmithKline Clinical Genetics
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare, Erlangen, Germany
- 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
- Danish Strategic Research Council
- Stanley Research Foundation
- European Union [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]
- NIMH
- National Alliance for Research on Schizophrenia and Depression
- BBSRC
- MRC
- German Federal Ministry of Education and Research
- European Union (FP 7)
- Interdisciplinary Center for Clinical Research Munster
- National Health and Medical Research Council 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
- Federal Ministry of Education
- Research Germany and speakers honoraria from Eli Lilly and Servier
- Medical Research Council (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 [NOW VENI 916-76-125]
- MRC [MC_PC_U127561128] Funding Source: UKRI
- Chief Scientist Office [CZD/16/6/4] Funding Source: researchfish
- Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561128, MR/K026992/1, 1292844] Funding Source: researchfish
Ask authors/readers for more resources
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 = 5.2 x 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.
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