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Am J Psychiatry. 2019 Jun 5:appiajp201918080957. doi: 10.1176/appi.ajp.2019.18080957. [Epub ahead of print]

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

Mullins N1, Bigdeli TB1, Børglum AD1, Coleman JRI1, Demontis D1, Mehta D1, Power RA1, Ripke S1, Stahl EA1, Starnawska A1, Anjorin A1; M.R.C.Psych1, Corvin A1, Sanders AR1, Forstner AJ1, Reif A1, Koller AC1, Świątkowska B1, Baune BT1, Müller-Myhsok B1, Penninx BWJH1, Pato C1, Zai C1, Rujescu D1, Hougaard DM1, Quested D1, Levinson DF1, Binder EB1, Byrne EM1, Agerbo E1; Dr.Med.Sc1, Streit F1, Mayoral F1, Bellivier F1, Degenhardt F1, Breen G1, Morken G1, Turecki G1, Rouleau GA1, Grabe HJ1, Völzke H1, Jones I1, Giegling I1, Agartz I1, Melle I1, Lawrence J1; M.R.C.Psych1, Walters JTR1, Strohmaier J1, Shi J1, Hauser J1, Biernacka JM1, Vincent JB1, Kelsoe J1, Strauss JS1, Lissowska J1, Pimm J1; M.R.C.Psych1, Smoller JW1, Guzman-Parra J1, Berger K1, Scott LJ1, Jones LA1, Azevedo MH1, Trzaskowski M1, Kogevinas M1, Rietschel M1, Boks M1, Ising M1, Grigoroiu-Serbanescu M1, Hamshere ML1, Leboyer M1, Frye M1, Nöthen MM1, Alda M1, Preisig M1, Nordentoft M1, Boehnke M1, O'Donovan MC1, Owen MJ1, Pato MT1, Renteria ME1, Budde M1; Dipl.-Psych1, Weissman MM1, Wray NR1, Bass N1; M.R.C.Psych1, Craddock N1, Smeland OB1, Andreassen OA1, Mors O1, Gejman PV1, Sklar P1, McGrath P1, Hoffmann P1, McGuffin P1, Lee PH1, Mortensen PB1, Kahn RS1, Ophoff RA1, Adolfsson R1, Van der Auwera S1, Djurovic S1, Kloiber S1, Heilmann-Heimbach S1, Jamain S1, Hamilton SP1, McElroy SL1, Lucae S1, Cichon S1, Schulze TG1, Hansen T1, Werge T1, Air TM1, Nimgaonkar V1, Appadurai V1, Cahn W1, Milaneschi Y1; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium1; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium1; Schizophrenia Working Group of the Psychiatric Genomics Consortium1, Fanous AH1, Kendler KS1, McQuillin A1, Lewis CM1.

Author information

1
Social Genetic and Developmental Psychiatry Centre, King's College London (Mullins, Coleman, R.A. Mehta, Breen, McGuffin, Lewis); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (Mullins, Stahl, Sklar); Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, (Bigdeli, Fanous); Department of Psychiatry, Virginia Commonwealth University, Richmond, Va. (Bigdeli, Fanous, Kendler); Department of Biomedicine, Aarhus University, Aarhus, Denmark (Børglum, Demontis, Starnawska); iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Børglum, Demontis, Starnawska, Mortensen); iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark (Børglum, Demontis, Starnawska, Hougaard, Agerbo, Nordentoft, Mors, Mortensen, Hansen, Werge, Appadurai); Queensland Brain Institute, the University of Queensland, Brisbane, Queensland, Australia (D. Mehta, Wray); School of Psychology and Counseling, Queensland University of Technology, Brisbane, Queensland, Australia (D. Mehta); Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Ripke, Lee); Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany (Ripke); Medical and Population Genetics, Broad Institute, Cambridge, Mass. (Ripke, Stahl); Department of Psychiatry and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (Stahl, Sklar, Kahn); Psychiatry, Berkshire Healthcare NHS Foundation Trust, Bracknell, U.K. (Anjorin); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland (Corvin); Department of Psychiatry and Behavioral Neuroscience, University of Chicago (Sanders, Gejman); Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Ill. (Sanders, Gejman); Department of Psychiatry (UPK), University of Basel, Basel, Switzerland (Forstner); Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland (Forstner, Hoffmann, Cichon); Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland (Forstner); Institute of Human Genetics, University of Bonn, Germany (Forstner, Koller, Degenhardt, Nöthen, Hoffmann, Cichon); Life and Brain Center, Department of Genomics, University of Bonn, Germany (Forstner, Koller, Degenhardt, Nöthen, Hoffmann); Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany (Reif); Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland (Świątkowska); Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Australia (Baune); Department of Psychiatry, University of Münster, Münster, Germany (Baune); University of Liverpool, Liverpool, U.K. (Müller-Myhsok); Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany (Müller-Myhsok, Binder); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (Müller-Myhsok); Department of Psychiatry, University of Halle, Halle, Germany (Rujescu, Giegling); Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands (Penninx, Milaneschi); College of Medicine Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, New York (C. Pato); Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, New York (C. Pato, M.T. Pato); Centre for Addiction and Mental Health, Toronto (Zai, Vincent, Strauss, Kloiber); Department of Psychiatry, University of Munich, Munich, Germany (Rujescu, Giegling); Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark (Hougaard); Department of Psychiatry, University of Oxford, Oxford, U.K. (Quested); Psychiatry & Behavioral Sciences, Stanford University, Stanford, Calif. (Levinson); Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga. (Binder); Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia (Byrne, Trzaskowski, Wray); Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark (Agerbo, Mortensen); National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark (Agerbo, Mortensen); Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (Streit, Strohmaier, Schulze); Mental Health Department, University Regional Hospital. Biomedicine Institute (IBIMA), Málaga, Spain (Mayoral, Guzman-Parra); Department of Psychiatry and Addiction Medicine, Assistance Publique-Hôpitaux de Paris, Paris (Bellivier, Leboyer); Paris Bipolar and TRD Expert Centres, FondaMental Foundation, Paris (Bellivier); UMR-S1144 Team 1: Biomarkers of relapse and therapeutic response in addiction and mood disorders, INSERM, Paris (Bellivier); Psychiatry, Université Paris Diderot, Paris (Bellivier); NIHR Maudsley Biomedical Research Centre, King's College London (Breen); Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology-NTNU, Trondheim, Norway (Morken); Psychiatry, St. Olavs University Hospital, Trondheim, Norway (Morken); Department of Psychiatry, McGill University, Montreal (Turecki); Department of Neurology and Neurosurgery, McGill University, Faculty of Medicine, Montreal. (Rouleau); Montreal Neurological Institute and Hospital (Rouleau); Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany (Grabe, Van der Auwera); Institute for Community Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany (Völzke); Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, U.K. (Jones, Hamshere, O'Donovan, Owen, Craddock); Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway (Agartz); NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Norway (Agartz); Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden (Agartz); Division of Mental Health and Addiction, Oslo University Hospital (Melle); Division of Mental Health and Addiction, University of Oslo, Institute of Clinical Medicine, Oslo (Melle); Psychiatry, North East London NHS Foundation Trust, Ilford, U.K. (Lawrence); MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, U.K. (Walters); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md. (Shi); Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland (Hauser); Health Sciences Research, Mayo Clinic, Rochester, Minn. (Biernacka); Department of Psychiatry, University of California San Diego, La Jolla, Calif. (Kelsoe); Department of Psychiatry, University of Toronto (Strauss, Kloiber); Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland (Lissowska); Division of Psychiatry, University College London (Pimm, Bass, McQuillin); Department of Psychiatry, Massachusetts General Hospital, Boston (Smoller); Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston Smoller); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass (Smoller, Lee); Institute of Epidemiology and Social Medicine, University of Münster, Münster, Nordrhein-Westfalen, Germany (Berger); Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor (Scott, Boehnke); Department of Psychological Medicine, University of Worcester, Worcester, U.K. (Jones); Department of Psychiatry, University of Coimbra, Coimbra, Portugal (Azevedo); Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain (Kogevinas); Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany (Rietschel); Psychiatry, UMC Utrecht Hersencentrum Rudolf Magnus, Utrecht, the Netherlands (Boks, Kahn); Max Planck Institute of Psychiatry, Munich, Germany (Ising, Kloiber, Lucae); Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania (Grigoroiu-Serbanescu); Faculté de Médecine, Université Paris Est, Créteil, France (Leboyer, Jamain); INSERM, Paris (Leboyer); Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minn. (Frye); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Alda); National Institute of Mental Health, Klecany, Czech Republic (Alda); Department of Psychiatry, University Hospital of Lausanne, Prilly, Vaud, Switzerland (Preisig); Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark (Nordentoft); Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (Renteria); Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Munich, Germany (Budde, Schulze); Psychiatry, Columbia University College of Physicians and Surgeons, New York (Weissman, McGrath); Division of Epidemiology, New York State Psychiatric Institute, New York (Weissman); Department of Neurosciences, University of California San Diego, La Jolla, Calif. (Smeland); Division of Mental Health and Addiction, Oslo University Hospital (Smeland, Andreassen); NORMENT, University of Oslo (Smeland, Andreassen); Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark (Mors); Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Sklar); Department of Biomedicine, University of Basel, Basel, Switzerland (Hoffmann, Cichon); Psychiatric and Neurodevelopmental Genetics Unit, Mass. General Hospital, Boston (Lee); Jane and Terry Semel Institute for Neuroscience and Human Behavior, Los Angeles (Ophoff); UMC Utrecht Hersencentrum Rudolf Magnus, Utrecht, the Netherlands (Ophoff); Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden (Adolfsson); NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway (Djurovic); Department of Medical Genetics, Oslo University Hospital Ullevål, (Djurovic); Department of Biomedicine, University of Basel, Basel, Switzerland (Heilmann-Heimbach); Psychiatrie Translationnelle, Inserm U955, Créteil, France (Jamain); Psychiatry, Kaiser Permanente Northern California, San Francisco (Hamilton); Research Institute, Lindner Center of HOPE, Mason, Ohio, (McElroy); Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany (Cichon); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md. (Schulze); Human Genetics Branch, Intramural Research Program, NIMH, Bethesda, Md. (Schulze); Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Goettingen, Niedersachsen, Germany (Schulze); Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen (Hansen); Department of Clinical Medicine, University of Copenhagen (Werge); Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark (Werge); Discipline of Psychiatry, University of Adelaide, Adelaide, Australia (Air); Psychiatry and Human Genetics, University of Pittsburgh (Nimgaonkar); Department of Psychiatry, UMC Utrecht Hersencentrum Rudolf Magnus, Utrecht, the Netherlands (Cahn); Department of Medical & Molecular Genetics, King's College London (Lewis).

Abstract

OBJECTIVE:

More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.

METHODS:

The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.

RESULTS:

Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).

CONCLUSIONS:

This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

KEYWORDS:

Genome-Wide Association Study; Mood Disorders; Polygenic Risk Scoring; Psychiatric Genomics Consortium; Schizophrenia; Suicide

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