[en] Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.
Disciplines :
Genetics & genetic processes
Author, co-author :
Grotzinger, Andrew D ; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. andrew.grotzinger@colorado.edu ; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA. andrew.grotzinger@colorado.edu
Werme, Josefin; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Peyrot, Wouter J; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands ; Department of Psychiatry, Amsterdam UMC, Amsterdam, The Netherlands
Frei, Oleksandr ; Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway ; NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
de Leeuw, Christiaan ; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Bicks, Lucy K; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Guo, Qiuyu; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA ; Discovery Biomarker, Amgen, Thousand Oaks, CA, USA
Margolis, Michael P; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA ; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Coombes, Brandon J; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
Batzler, Anthony; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
Pazdernik, Vanessa; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
Biernacka, Joanna M ; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA ; Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA
Andreassen, Ole A ; NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway ; KG Jebsen Centre for Neurodevelopment, University of Oslo, Oslo, Norway
Anttila, Verneri; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Børglum, Anders D ; Center for Genomics and Personalized Medicine, CGPM, Aarhus, Denmark ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; The Lundbeck Foundation Initiative for Integrative Psychiatric Research-iPSYCH, Aarhus, Denmark
Breen, Gerome ; Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK
Cai, Na; Computational Health Centre, Helmholtz Munich, Neuherberg, Germany ; Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland ; Department of Medicine, Technical University of Munich, Munich, Germany ; Helmholtz Pioneer Campus, Helmholtz Munich, Neuherberg, Germany
Demontis, Ditte ; Center for Genomics and Personalized Medicine, CGPM, Aarhus, Denmark ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; The Lundbeck Foundation Initiative for Integrative Psychiatric Research-iPSYCH, Aarhus, Denmark ; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Edenberg, Howard J ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Faraone, Stephen V; Department of Neuroscience and Physiology, Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA ; Department of Psychiatry, Norton College of Medicine, SUNY Upstate Medical Universitiy, Syracuse, NY, USA
Franke, Barbara ; Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands ; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
Gandal, Michael J ; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA ; Lifespan Brain Institute at Penn Med and the Children's Hospital of Philadelphia, Philadelphia, PA, USA
Gelernter, Joel ; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA ; VA Connecticut Healthcare Center, West Haven, CT, USA
Hatoum, Alexander S ; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
Hettema, John M; Department of Psychiatry and Behavioral Sciences, Texas A&M University, College Station, TX, USA
Johnson, Emma C ; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
Jonas, Katherine G ; Department of Psychiatry & Behavioral Health, Stony Brook University, New York, NY, USA
Knowles, James A; Department of Genetics, Rutgers University, Piscataway, NJ, USA ; Human Genetics Institute of New Jersey (HGINJ), Rutgers University, Piscataway, NJ, USA
Koenen, Karestan C; Broad Institute of MIT and Harvard, Boston, MA, USA ; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA ; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Maihofer, Adam X; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA ; Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA ; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
Mallard, Travis T ; Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA ; Department of Psychiatry, Harvard Medical School, Boston, MA, USA ; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Mattheisen, Manuel ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm, Sweden ; Department of Community Health and Epidemiology and Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada ; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany
Mitchell, Karen S; Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA ; National Center for PTSD at VA Boston Healthcare System, Boston, MA, USA
Neale, Benjamin M ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Nievergelt, Caroline M; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA ; Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA ; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
Nurnberger, John I; Department of Medical and Molecular Genetics, Department of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
O'Connell, Kevin S; NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
Peterson, Roseann E ; Department of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, New York, NY, USA
Robinson, Elise B ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Sanchez-Roige, Sandra S; Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA ; Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA ; Institute for Genomic Medicine, University of California San Diego, San Diego, CA, USA
Santangelo, Susan L ; Center for Clinical and Translational Science, Maine Health Institute for Research, Portland, ME, USA ; Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA
Scharf, Jeremiah M; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA ; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA ; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
Stefansson, Kari; Amgen-deCODE Genetics, Reykjavik, Iceland ; Faculty of Medicine, University of Iceland, Reykjavík, Iceland
Stein, Murray B ; Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA ; Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA ; VA San Diego Healthcare System, San Diego, CA, USA
Strom, Nora I ; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm, Sweden ; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany ; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
Thornton, Laura M; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Tucker-Drob, Elliot M ; Center on Aging and Population Sciences, University of Texas at Austin, Austin, TX, USA ; Department of Psychology, University of Texas at Austin, Austin, TX, USA ; Population Research Center, University of Texas at Austin, Austin, TX, USA
Verhulst, Brad; Department of Psychiatry and Behavioral Sciences, Texas A&M University, College Station, TX, USA
Waldman, Irwin D ; Department of Psychology, Emory University, Atlanta, GA, USA
Walters, G Bragi ; Amgen-deCODE Genetics, Reykjavik, Iceland ; Faculty of Medicine, University of Iceland, Reykjavík, Iceland
Wray, Naomi R ; Department of Psychiatry, University of Oxford, Oxford, UK ; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
Yu, Dongmei; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA ; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
Anxiety Disorders Working Group of the Psychiatric Genomics Consortium
Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group of the Psychiatric Genomics Consortium
Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium
Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Eating Disorders Working Group of the Psychiatric Genomics Consortium
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Nicotine Dependence GenOmics (iNDiGO) Consortium
Obsessive-Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium
Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Substance Use Disorders Working Group of the Psychiatric Genomics Consortium
Lee, Phil H ; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Kendler, Kenneth S ; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA ; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
Smoller, Jordan W ; Broad Institute of MIT and Harvard, Boston, MA, USA. jsmoller@mgb.org ; Department of Psychiatry, Harvard Medical School, Boston, MA, USA. jsmoller@mgb.org ; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. jsmoller@mgb.org
Docampo Martínez, Elisa ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
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