Rare coding variants in ten genes confer substantial risk for schizophrenia.

Autor:	Singh T; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. tsingh@broadinstitute.org.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. tsingh@broadinstitute.org.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. tsingh@broadinstitute.org., Poterba T; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Curtis D; UCL Genetics Institute, University College London, London, UK.; Centre for Psychiatry, Queen Mary University London, London, UK., Akil H; Department of Psychiatry, Michigan Neuroscience Institute, Medical School, University of Michigan, Ann Arbor, MI, USA., Al Eissa M; Division of Psychiatry, University College London, London, UK., Barchas JD; Weill Cornell Medical College, New York, NY, USA., Bass N; Division of Psychiatry, University College London, London, UK., Bigdeli TB; Department of Psychiatry and Behavioral Sciences, SUNY Downstate College of Medicine, Brooklyn, NY, USA., Breen G; Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Bromet EJ; Department of Psychiatry and Behavioral Health, Health Sciences Center, Stony Brook University, Stony Brook, NY, USA., Buckley PF; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA., Bunney WE; Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA., Bybjerg-Grauholm J; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Byerley WF; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA., Chapman SB; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Chen WJ; College of Public Health, National Taiwan University, Taipei, Taiwan., Churchhouse C; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Craddock N; National Centre for Mental Health, Cardiff University, Cardiff, UK., Cusick CM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., DeLisi L; Department of Psychiatry, Cambridge Health Alliance, Cambridge Hospital, Cambridge, MA, USA., Dodge S; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Escamilla MA; Texas Tech University Health Sciences Center, El Paso, TX, USA., Eskelinen S; University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Public Health Solutions, Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland., Fanous AH; Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA., Faraone SV; Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA., Fiorentino A; Division of Psychiatry, University College London, London, UK., Francioli L; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Gabriel SB; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gage D; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gagliano Taliun SA; Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.; Montréal Heart Institute, Montreal, Quebec, Canada., Ganna A; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Genovese G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Glahn DC; Department of Psychiatry, Boston Children's Hospital, Boston, MA, USA., Grove J; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Department of Biomedicine and Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.; Center for Genomics and Personalized Medicine, Aarhus, Denmark.; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark., Hall MH; McLean Hospital, Harvard Medical School, Belmont, MA, USA., Hämäläinen E; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Heyne HO; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Holi M; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Hougaard DM; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Howrigan DP; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Huang H; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Hwu HG; Department of Psychiatry, National Taiwan University, Taipei, Taiwan., Kahn RS; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; MIRECC, JP Peters VA Hospital, Bronx, NY, USA., Kang HM; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Karczewski KJ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kirov G; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Knowles JA; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA., Lee FS; Weill Cornell Medical College, New York, NY, USA., Lehrer DS; Department of Psychiatry, Wright State University, Dayton, OH, USA., Lescai F; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Malaspina D; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Marder SR; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., McCarroll SA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., McIntosh AM; University of Edinburgh, Edinburgh, UK., Medeiros H; Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA., Milani L; Institute of Genomics, University of Tartu, Tartu, Estonia., Morley CP; Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.; Department of Public Health and Preventive Medicine and Department of Family Medicine, SUNY Upstate Medical University, Syracuse, NY, USA., Morris DW; National University of Ireland, Galway, Ireland., Mortensen PB; Aarhus University, Aarhus, Denmark., Myers RM; HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA., Nordentoft M; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Copenhagen Research Center for Mental Health, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., O'Brien NL; Division of Psychiatry, University College London, London, UK., Olivares AM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ongur D; McLean Hospital, Harvard Medical School, Belmont, MA, USA., Ouwehand WH; University of Cambridge, Cambridge, UK., Palmer DS; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Paunio T; Department of Psychiatry, University of Helsinki, Helsinki, Finland., Quested D; Oxford Health NHS Foundation Trust, Oxford, UK., Rapaport MH; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA., Rees E; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Rollins B; Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA., Satterstrom FK; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA., Schatzberg A; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Scolnick E; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Scott LJ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Sharp SI; Division of Psychiatry, University College London, London, UK., Sklar P; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Smoller JW; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Department of Psychiatry, Harvard Medical School, Boston, MA, USA., Sobell JL; Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Solomonson M; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Stahl EA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Stevens CR; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Suvisaari J; Finnish Institute for Health and Welfare, Helsinki, Finland., Tiao G; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Watson SJ; Department of Psychiatry, Michigan Neuroscience Institute, Medical School, University of Michigan, Ann Arbor, MI, USA., Watts NA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Blackwood DH; Department of Psychiatry, University of Edinburgh, Edinburgh, UK., Børglum AD; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Department of Biomedicine and Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.; Center for Genomics and Personalized Medicine, Aarhus, Denmark., Cohen BM; McLean Hospital, Harvard Medical School, Belmont, MA, USA., Corvin AP; Trinity College Dublin, Dublin, Ireland., Esko T; Institute of Genomics, University of Tartu, Tartu, Estonia., Freimer NB; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Glatt SJ; Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA., Hultman CM; School of Medicine, Johns Hopkins University, Baltimore, MD, USA., McQuillin A; Division of Psychiatry, University College London, London, UK., Palotie A; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Pato CN; Department of Psychiatry and Behavioral Sciences, SUNY Downstate College of Medicine, Brooklyn, NY, USA., Pato MT; Department of Psychiatry and Behavioral Sciences, SUNY Downstate College of Medicine, Brooklyn, NY, USA., Pulver AE; School of Medicine, Johns Hopkins University, Baltimore, MD, USA., St Clair D; University of Aberdeen, Aberdeen, UK., Tsuang MT; Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA., Vawter MP; Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA., Walters JT; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Werge TM; Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.; Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark., Ophoff RA; Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Psychiatry, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands., Sullivan PF; Karolinska Institute, Solna, Sweden.; University of North Carolina, Chapel Hill, NC, USA., Owen MJ; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Boehnke M; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., O'Donovan MC; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Neale BM; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. bneale@broadinstitute.org.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. bneale@broadinstitute.org., Daly MJ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. mjdaly@atgu.mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature [Nature] 2022 Apr; Vol. 604 (7906), pp. 509-516. Date of Electronic Publication: 2022 Apr 08.
DOI:	10.1038/s41586-022-04556-w
Abstrakt:	Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10 -6 ) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders 1 , epilepsy and severe neurodevelopmental disorders 2 , although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk 3 , suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
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