RT Journal Article T1 Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. A1 Power, Robert A A1 Tansey, Katherine E A1 Buttenschøn, Henriette Nørmølle A1 Cohen-Woods, Sarah A1 Bigdeli, Tim A1 Hall, Lynsey S A1 Kutalik, Zoltán A1 Lee, S Hong A1 Ripke, Stephan A1 Steinberg, Stacy A1 Teumer, Alexander A1 Viktorin, Alexander A1 Wray, Naomi R A1 Arolt, Volker A1 Baune, Bernard T A1 Boomsma, Dorret I A1 Børglum, Anders D A1 Byrne, Enda M A1 Castelao, Enrique A1 Craddock, Nick A1 Craig, Ian W A1 Dannlowski, Udo A1 Deary, Ian J A1 Degenhardt, Franziska A1 Forstner, Andreas J A1 Gordon, Scott D A1 Grabe, Hans J A1 Grove, Jakob A1 Hamilton, Steven P A1 Hayward, Caroline A1 Heath, Andrew C A1 Hocking, Lynne J A1 Homuth, Georg A1 Hottenga, Jouke J A1 Kloiber, Stefan A1 Krogh, Jesper A1 Landén, Mikael A1 Lang, Maren A1 Levinson, Douglas F A1 Lichtenstein, Paul A1 Lucae, Susanne A1 MacIntyre, Donald J A1 Madden, Pamela A1 Magnusson, Patrik K E A1 Martin, Nicholas G A1 McIntosh, Andrew M A1 Middeldorp, Christel M A1 Milaneschi, Yuri A1 Montgomery, Grant W A1 Mors, Ole A1 Müller-Myhsok, Bertram A1 Nyholt, Dale R A1 Oskarsson, Hogni A1 Owen, Michael J A1 Padmanabhan, Sandosh A1 Penninx, Brenda W J H A1 Pergadia, Michele L A1 Porteous, David J A1 Potash, James B A1 Preisig, Martin A1 Rivera, Margarita A1 Shi, Jianxin A1 Shyn, Stanley I A1 Sigurdsson, Engilbert A1 Smit, Johannes H A1 Smith, Blair H A1 Stefansson, Hreinn A1 Stefansson, Kari A1 Strohmaier, Jana A1 Sullivan, Patrick F A1 Thomson, Pippa A1 Thorgeirsson, Thorgeir E A1 Van der Auwera, Sandra A1 Weissman, Myrna M A1 CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium A1 Breen, Gerome A1 Lewis, Cathryn M K1 Age at onset K1 GWAS K1 Heterogeneity K1 Major depressive disorder K1 Polygenic scoring K1 Stratification AB 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. 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. 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 × 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. 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. YR 2016 FD 2016-05-24 LK http://hdl.handle.net/10668/10357 UL http://hdl.handle.net/10668/10357 LA en DS RISalud RD Feb 16, 2025