title: Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.
abstract: 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.
authors: Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London.
authors: Robert A
authors: RA
authors: Power
authors: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Katherine E
authors: KE
authors: Tansey
authors: Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors: Henriette Nørmølle
authors: HN
authors: Buttenschøn
authors: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
authors: Sarah
authors: S
authors: Cohen-Woods
authors: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors: Tim
authors: T
authors: Bigdeli
authors: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors: Lynsey S
authors: LS
authors: Hall
authors: Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Zoltán
authors: Z
authors: Kutalik
authors: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland; School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.
authors: S Hong
authors: SH
authors: Lee
authors: Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
authors: Stephan
authors: S
authors: Ripke
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Stacy
authors: S
authors: Steinberg
authors: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors: Alexander
authors: A
authors: Teumer
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Alexander
authors: A
authors: Viktorin
authors: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland.
authors: Naomi R
authors: NR
authors: Wray
authors: Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
authors: Volker
authors: V
authors: Arolt
authors: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
authors: Bernard T
authors: BT
authors: Baune
authors: Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
authors: Dorret I
authors: DI
authors: Boomsma
authors: Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Department of Biomedicine and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors: Anders D
authors: AD
authors: Børglum
authors: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland.
authors: Enda M
authors: EM
authors: Byrne
authors: Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors: Enrique
authors: E
authors: Castelao
authors: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Nick
authors: N
authors: Craddock
authors: Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London.
authors: Ian W
authors: IW
authors: Craig
authors: Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany; Department of Psychiatry, University of Marburg, Marburg, Germany.
authors: Udo
authors: U
authors: Dannlowski
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Ian J
authors: IJ
authors: Deary
authors: Institute of Human Genetics; Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Franziska
authors: F
authors: Degenhardt
authors: Institute of Human Genetics; Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Andreas J
authors: AJ
authors: Forstner
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: Scott D
authors: SD
authors: Gordon
authors: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors: Hans J
authors: HJ
authors: Grabe
authors: Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Department of Biomedicine and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors: Jakob
authors: J
authors: Grove
authors: Department of Psychiatry, Kaiser Permanente San Francisco Medical Center, San Francisco, California.
authors: Steven P
authors: SP
authors: Hamilton
authors: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors: Caroline
authors: C
authors: Hayward
authors: Department of Psychiatry, Washington University St. Louis, St. Louis, Missouri.
authors: Andrew C
authors: AC
authors: Heath
authors: Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors: Lynne J
authors: LJ
authors: Hocking
authors: Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald.
authors: Georg
authors: G
authors: Homuth
authors: Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
authors: Jouke J
authors: JJ
authors: Hottenga
authors: Max Planck Institute of Psychiatry, Munich, Germany.
authors: Stefan
authors: S
authors: Kloiber
authors: Mental Health Center Copenhagen, Mental Health Services in Capital Region, University of Copenhagen, Copenhagen, Denmark.
authors: Jesper
authors: J
authors: Krogh
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors: Mikael
authors: M
authors: Landén
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors: Maren
authors: M
authors: Lang
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
authors: Douglas F
authors: DF
authors: Levinson
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Paul
authors: P
authors: Lichtenstein
authors: Max Planck Institute of Psychiatry, Munich, Germany.
authors: Susanne
authors: S
authors: Lucae
authors: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors: Donald J
authors: DJ
authors: MacIntyre
authors: Department of Psychiatry, Washington University St. Louis, St. Louis, Missouri.
authors: Pamela
authors: P
authors: Madden
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Patrik K E
authors: PKE
authors: Magnusson
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom.
authors: Andrew M
authors: AM
authors: McIntosh
authors: Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
authors: Christel M
authors: CM
authors: Middeldorp
authors: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Yuri
authors: Y
authors: Milaneschi
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: Grant W
authors: GW
authors: Montgomery
authors: Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
authors: Ole
authors: O
authors: Mors
authors: Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Bertram
authors: B
authors: Müller-Myhsok
authors: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors: Dale R
authors: DR
authors: Nyholt
authors: Therapeia, Reykjavik, Iceland.
authors: Hogni
authors: H
authors: Oskarsson
authors: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors: Michael J
authors: MJ
authors: Owen
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Sandosh
authors: S
authors: Padmanabhan
authors: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Brenda W J H
authors: BWJH
authors: Penninx
authors: Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida.
authors: Michele L
authors: ML
authors: Pergadia
authors: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors: David J
authors: DJ
authors: Porteous
authors: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: James B
authors: JB
authors: Potash
authors: Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors: Martin
authors: M
authors: Preisig
authors: Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London; CIBERSAM-Universidad de Granada e Instituto de Investigación Biosanitaria ibs, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
authors: Margarita
authors: M
authors: Rivera
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors: Jianxin
authors: J
authors: Shi
authors: Department of Psychiatry, Group Health, Seattle, Washington.
authors: Stanley I
authors: SI
authors: Shyn
authors: University of Iceland; Department of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland.
authors: Engilbert
authors: E
authors: Sigurdsson
authors: Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Johannes H
authors: JH
authors: Smit
authors: Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
authors: Blair H
authors: BH
authors: Smith
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Hreinn
authors: H
authors: Stefansson
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Kari
authors: K
authors: Stefansson
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors: Jana
authors: J
authors: Strohmaier
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors: Patrick F
authors: PF
authors: Sullivan
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors: Pippa
authors: P
authors: Thomson
authors: deCODE Genetics, Reykjavik, Iceland.
authors: Thorgeir E
authors: TE
authors: Thorgeirsson
authors: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors: Sandra
authors: S
authors: Van der Auwera
authors: College of Physicians and Surgeons and the Mailman School of Public Health, Columbia University and New York State Psychiatric Institute, New York, New York.
authors: Myrna M
authors: MM
authors: Weissman
authors: Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London.
authors: Gerome
authors: G
authors: Breen
authors: Institute of Psychiatry, Psychology, and Neuroscience, King׳s College London, London. Electronic address: cathryn.lewis@kcl.ac.uk.
authors: Cathryn M
authors: CM
authors: Lewis
mesh_terms: D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult
keywords: Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic scoring; Stratification