Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
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AuthorPower, Robert A.; Rivera Sánchez, Margarita; CONVERGE Consortium; CARDIoGRAM Consortium; GERAD1 Consortium
Age at onsetGenome-wide association study (GWAS)HeterogeneityMajor depressive disorderPolygenic scoringStratification
Power, R. A., Tansey, K. E., Buttenschøn, H. N., Cohen-Woods, S., Bigdeli, T., Hall, L. S., ... & Teumer, A. (2017). Genome-wide association for major depression through age at onset stratification: major depressive disorder working group of the psychiatric genomics consortium. Biological Psychiatry, 81(4), 325-335. [https://doi.org/10.1016/j.biopsych.2016.05.010]
SponsorshipUnited 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
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.