title: Genetic effects influencing risk for major depressive disorder in China and Europe.
abstract: Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Department of Psychiatry, Charite Universitatsmedizin Berlin Campus Benjamin Franklin, Berlin, Germany.|Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Peterson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Trzaskowski
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: S-A
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Abdellaoui
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: T F M
authors.initials: TF
authors.lastname: Andlauer
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: A T F
authors.initials: AT
authors.lastname: Beekman
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Berger
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: D H R
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: King's College London, NIHR BRC for Mental Health, London, UK.|King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
authors.forename: H N
authors.initials: HN
authors.lastname: Buttenschøn
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: E M
authors.initials: EM
authors.lastname: Byrne
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Division of Medical Genetics, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Jülich, Germany.|Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: T-K
authors.initials: TK
authors.lastname: Clarke
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Couvy-Duchesne
authors.affiliation: Department of Psychological Medicine, Cardiff University, Cardiff, UK.
authors.forename: N
authors.initials: N
authors.lastname: Craddock
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.|EMGO+ Institute, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E J C
authors.initials: EJ
authors.lastname: de Geus
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Dunn
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Edwards
authors.affiliation: Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Fanous
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: S D
authors.initials: SD
authors.lastname: Gordon
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Department of Psychiatry, Kaiser-Permanente Northern California, San Fransisco, CA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Hamilton
authors.affiliation: Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: O
authors.initials: O
authors.lastname: Hardiman
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Herms
authors.affiliation: Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.
authors.forename: I B
authors.initials: IB
authors.lastname: Hickie
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Hottenga
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ising
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kloiber
authors.affiliation: Department of Psychiatry and The Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Knowles
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lang
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
authors.forename: Q S
authors.initials: QS
authors.lastname: Li
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lucae
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: MacIntyre
authors.affiliation: Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA.
authors.forename: P A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Psychology, University of Queensland, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: McGrath
authors.affiliation: King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Mehta
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Middeldorp
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Milaneschi
authors.affiliation: Institute for Molecular Biology, University of Queensland, Brisbane, QLD, Australia.
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Mors
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: B
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: D R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: B W J H
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Pergadia
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Perlis
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Peyrot
authors.affiliation: Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa, IA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Department of Psychiatry, Washington University in Saint Louis, St Louis, MO, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Rice
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.|Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Riley
authors.affiliation: Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.|King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Rivera
authors.affiliation: Department of Psychiatry, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Schoevers
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.|Institute of Psychiatric Phenomics and Genomics, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, The Netherlands.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.|Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: Division of Psychiatry, Group Health, Seattle, WA, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Shyn
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Smit
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Streit
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Teumer
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Van der Auwera
authors.affiliation: Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van Grootheest
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: van Hemert
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Webb
authors.affiliation: Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.|Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Weissman
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wellmann
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: S H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Levinson
authors.affiliation: King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK.|King's College London, Department of Medical and Molecular Genetics, London, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: N R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Merton College, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Flint
authors.affiliation: Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.|Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Kendler
mesh_terms: D044466:Asian People / Q000235:genetics*; D001499:Bayes Theorem; D016022:Case-Control Studies; D002681:China; D003865:Major Depressive Disorder / Q000235:genetics*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*