Genetic effects influencing risk for major depressive disorder in China and Europe

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DOI

  • Tim B Bigdeli, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • S Ripke, 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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  • Roseann E Peterson, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • M Trzaskowski, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Silviu-Alin Bacanu, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • Abdel Abdellaoui, Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
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  • T F M Andlauer, 1] Statistical Genetics, Department of Translational Psychiatry, Max Planck Institute of Psychiatry, D-80804 Munich, Germany [2] Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany [3] Institute of Translational Medicine, University of Liverpool, L69 3BX Liverpool, UK.
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  • A T F Beekman, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • Klaus Berger, Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany.
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  • Douglas H R Blackwood, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
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  • Dorret I Boomsma, Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
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  • G Breen, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
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  • H N Buttenschøn
  • E M Byrne, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • S. Cichon, Institute of Human Genetics, University of Bonn, Bonn, Germany.
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  • Toni-Kim Clarke, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
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  • B Couvy-Duchesne, Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
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  • N. Craddock, From the *National Centre for Register-based Research; †CRESTAR, Aarhus University, Aarhus, Denmark; ‡Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark; §Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff; ∥Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom; ¶Centre for Integrated Register-Based Research at Aarhus University (CIRRAU); and #iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
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  • Eco J C de Geus, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • F. Degenhardt, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
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  • Erin C Dunn, 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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  • A.C. Edwards, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • Ayman H Fanous, Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
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  • A J Forstner, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
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  • J Frank, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • M. Gill, Neuropsychiatric Genetics Group, Department of Psychiatry, Trinity College Dublin, St James Hospital, Dublin, Ireland.
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  • Scott D Gordon, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.
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  • Hans J Grabe, Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
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  • Steven P Hamilton, Department of Psychiatry, Kaiser-Permanente Northern California, San Fransisco, CA, USA.
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  • Orla Hardiman, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
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  • Carolyn Hayward, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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  • Andrew C Heath, Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA.
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  • Anjali K Henders, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • S. Herms, z Division of Medical Genetics, Department of Biomedicine , University of Basel , Basel , Switzerland.
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  • Ian B Hickie, Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.
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  • P Hoffmann, Institute of Human Genetics, University of Bonn, Bonn, Germany., 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany., Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
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  • Georg Homuth, Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
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  • Jouke-Jan Hottenga, Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
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  • M Ising, Max Planck Institute of Psychiatry, Munich, Germany.
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  • Colin R. Jansen, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • S Kloiber, Max Planck Institute of Psychiatry, Munich, Germany.
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  • James A Knowles, Department of Psychiatry and The Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
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  • M Lang
  • Q S Li, Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
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  • S Lucae, Max Planck Institute of Psychiatry, Munich, Germany.
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  • Donald J Macintyre, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
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  • Pamela A F Madden, Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA.
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  • N G Martin, School of Psychology, University of Queensland, Brisbane, QLD, Australia.
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  • Patrick J. McGrath, 1] Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA. [4] Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
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  • P McGuffin, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
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  • Andrew M McIntosh, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK.
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  • S E Medland, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.
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  • D. Mehta, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • Christel M Middeldorp, Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
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  • Yuri Milaneschi, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • G W Montgomery, Institute for Molecular Biology, University of Queensland, Brisbane, QLD, Australia.
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  • O Mors
  • B Müller-Myhsok, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
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  • M A Nauck, Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.
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  • Dale R Nyholt, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
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  • M M Nöthen, 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
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  • M J Owen, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
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  • Brenda W J H Penninx, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • Michele L Pergadia, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
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  • R H Perlis, Department of Psychiatry, Massachusetts General Hospital, Boston, Masschusetts, USA.
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  • W J Peyrot, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • D J Porteous, Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK.
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  • James B Potash, Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA.
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  • John P Rice, Department of Psychiatry, Washington University in Saint Louis, St Louis, MO, USA.
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  • M Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Brien P Riley, Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • M. Rivera, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
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  • R Schoevers, Department of Psychiatry, University of Groningen, University Medical Center Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.
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  • T G Schulze, Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA.
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  • J. Shi, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
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  • Stanley I Shyn, Division of Psychiatry, Group Health, Seattle, WA, USA.
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  • J H Smit
  • Jordan W Smoller, 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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  • Fabian Streit, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • J. Strohmaier, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Alexander Teumer, 1] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany.
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  • J Treutlein, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Sandra Van der Auwera, Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
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  • Gerard Van Grootheest, Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
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  • A M van Hemert, Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
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  • Henry Völzke, 1] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany.
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  • Bradley Todd Webb, Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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  • Myrna M Weissman, 1] Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2] Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA. [4] Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
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  • Juergen Wellmann, Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany.
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  • Gonneke Willemsen, Department of Biological Psychology, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.
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  • S H Witt, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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  • Douglas F Levinson, Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
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  • C M Lewis, Department of Medical and Molecular Genetics, King's College London, London, UK.
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  • Naomi R Wray, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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  • J. Flint, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
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  • P F Sullivan, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • Kenneth S Kendler, Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

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; log10 Bayes 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.

Original languageEnglish
JournalTranslational Psychiatry
Volume7
Issue3
Pages (from-to)e1074
ISSN2158-3188
DOIs
Publication statusPublished - 28 Mar 2017

    Research areas

  • Journal Article

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