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Title: Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Contributor(s): Power, Robert A (author); Tansey, Katherine E (author); Buttenschon, Henriette Normolle (author); Cohen-Woods, Sarah (author); Bigdeli, Tim (author); Hall, Lynsey S (author); Kutalik, Zoltn (author); Lee, Sang Hong  (author); Ripke, Stephan (author); Steinberg, Stacy (author); Teumer, Alexander (author); Viktorin, Alexander (author); Wray, Naomi R (author); Arolt, Volker (author); Baune, Bernard T (author); Boomsma, Dorret I (author); Borglum, Anders D (author); Byrne, Enda M (author); Castelao, Enrique (author); Craddock, Nick (author); Craig, Ian W (author); Dannlowski, Udo (author); Deary, Ian J (author); Degenhardt, Franziska (author); Forstner, Andreas J (author); Gordon, Scott D (author); Grabe, Hans J (author); Grove, Jakob (author); Hamilton, Steven P (author); Hayward, Caroline (author); Heath, Andrew C (author); Hocking, Lynne J (author); Homuth, Georg (author); Hottenga, Jouke J (author); Kloiber, Stefan (author); Krogh, Jesper (author); Landen, Mikael (author); Lang, Maren (author); Levinson, Douglas F (author); Lichtenstein, Paul (author); Lucae, Susanne (author); MacIntyre, Donald J (author); Madden, Pamela (author); Magnusson, Patrik K. E (author); Martin, Nicholas G (author); McIntosh, Andrew M (author); Middeldorp, Christel M (author); Milaneschi, Yuri (author); Montgomery, Grant W (author); Mors, Ole (author); Muller-Myhsok, Bertram (author); Nyholt, Dale R (author); Oskarsson, Hogni (author); Owen, Michael J (author); Padmanabhan, Sandosh (author); Penninx, Brenda W. J. H (author); Pergadia, Michele L (author); Porteous, David J (author); Potash, James B (author); Preisig, Martin (author); Rivera, Margarita (author); Shi, Jianxin (author); Shyn, Stanley I (author); Sigurdsson, Engilbert (author); Smit, Johannes H (author); Smith, Blair H (author); Stefansson, Hreinn (author); Stefansson, Kari (author); Strohmaier, Jana (author); Sullivan, Patrick F (author); Thomson, Pippa (author); Thorgeirsson, Thorgeir E (author); Van der Auwera, Sandra (author); Weissman, Myrna M (author); Breen, Gerome (author); Lewis, Cathryn M (author)
Corporate Author: China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology Consortium (CONVERGE)
Coronary ARtery DIsease Genome wide Replication and Meta-analysis Consortium (CARDIoGRAM)
Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD1)
Publication Date: 2017-02-15
Early Online Version: 2016-05-24
Open Access: Yes
DOI: 10.1016/j.biopsych.2016.05.010Open Access Link
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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 × 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.

Publication Type: Journal Article
Grant Details: NHMRC/241944
Source of Publication: Biological Psychiatry, 81(4), p. 325-335
Publisher: Elsevier Inc
Place of Publication: United States of America
ISSN: 1873-2402
Fields of Research (FoR) 2020: 320213 Medical genetics (excl. cancer genetics)
Socio-Economic Objective (SEO) 2020: 280102 Expanding knowledge in the biological sciences
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
Appears in Collections:Journal Article
School of Environmental and Rural Science

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