TY - JOUR
T1 - Genome-wide Association for Major Depression Through Age at Onset Stratification
T2 - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium
AU - Power, Robert A.
AU - Tansey, Katherine E.
AU - Buttenschøn, Henriette Nørmølle
AU - Cohen-Woods, Sarah
AU - Bigdeli, Tim
AU - Hall, Lynsey S.
AU - Kutalik, Zoltán
AU - Lee, S. Hong
AU - Ripke, Stephan
AU - Steinberg, Stacy
AU - Teumer, Alexander
AU - Viktorin, Alexander
AU - Wray, Naomi R.
AU - Arolt, Volker
AU - Baune, Bernard T.
AU - Boomsma, Dorret I.
AU - Børglum, Anders D.
AU - Byrne, Enda M.
AU - Castelao, Enrique
AU - Craddock, Nick
AU - Craig, Ian W.
AU - Dannlowski, Udo
AU - Deary, Ian J.
AU - Degenhardt, Franziska
AU - Forstner, Andreas J.
AU - Gordon, Scott D.
AU - Grabe, Hans J.
AU - Grove, Jakob
AU - Hamilton, Steven P.
AU - Hayward, Caroline
AU - Heath, Andrew C.
AU - Hocking, Lynne J.
AU - Homuth, Georg
AU - Hottenga, Jouke J.
AU - Kloiber, Stefan
AU - Krogh, Jesper
AU - Landén, Mikael
AU - Lang, Maren
AU - Levinson, Douglas F.
AU - Lichtenstein, Paul
AU - Lucae, Susanne
AU - MacIntyre, Donald J.
AU - Madden, Pamela
AU - Magnusson, Patrik K.E.
AU - Martin, Nicholas G.
AU - McIntosh, Andrew M.
AU - Middeldorp, Christel M.
AU - Milaneschi, Yuri
AU - Montgomery, Grant W.
AU - Mors, Ole
AU - Müller-Myhsok, Bertram
AU - Nyholt, Dale R.
AU - Oskarsson, Hogni
AU - Owen, Michael J.
AU - Padmanabhan, Sandosh
AU - Penninx, Brenda W.J.H.
AU - Pergadia, Michele L.
AU - Porteous, David J.
AU - Potash, James B.
AU - Preisig, Martin
AU - Rivera, Margarita
AU - Shi, Jianxin
AU - Shyn, Stanley I.
AU - Sigurdsson, Engilbert
AU - Smit, Johannes H.
AU - Smith, Blair H.
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Strohmaier, Jana
AU - Sullivan, Patrick F.
AU - Thomson, Pippa
AU - Thorgeirsson, Thorgeir E.
AU - Van der Auwera, Sandra
AU - Weissman, Myrna M.
AU - Breen, Gerome
AU - Lewis, Cathryn M.
N1 - Publisher Copyright:
© 2016 Society of Biological Psychiatry
PY - 2017/2/15
Y1 - 2017/2/15
N2 - 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.
AB - 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.
KW - Age at onset
KW - GWAS
KW - Heterogeneity
KW - Major depressive disorder
KW - Polygenic scoring
KW - Stratification
UR - http://www.scopus.com/inward/record.url?scp=84994229145&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2016.05.010
DO - 10.1016/j.biopsych.2016.05.010
M3 - Article
C2 - 27519822
AN - SCOPUS:84994229145
SN - 0006-3223
VL - 81
SP - 325
EP - 335
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 4
ER -