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Rare coding variants in ten genes confer substantial risk for schizophrenia

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Tarjinder Singh, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Massachusetts General Hospital
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  • Timothy Poterba, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • David Curtis, University College London, Queen Mary University of London
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  • Huda Akil, University of Michigan, Ann Arbor
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  • Mariam Al Eissa, University College London
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  • Jack D. Barchas, Cornell University
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  • Nicholas Bass, University College London
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  • Tim B. Bigdeli, SUNY Downstate Medical Center
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  • Gerome Breen, King's College London
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  • Evelyn J. Bromet, Stony Brook University
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  • Peter F. Buckley, Virginia Commonwealth University
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  • William E. Bunney, University of California at Irvine
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  • Jonas Bybjerg-Grauholm, Statens Serum Institut, Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • William F. Byerley, University of California at San Francisco
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  • Sinéad B. Chapman, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Wei J. Chen, National Taiwan University
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  • Claire Churchhouse, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Nicholas Craddock, Cardiff University
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  • Caroline M. Cusick, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Lynn DeLisi, Cambridge Hospital, Cambridge Health Alliance, Cambridge, MA, USA
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  • Sheila Dodge, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Michael A. Escamilla, Texas Tech University Health Sciences Center El Paso
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  • Saana Eskelinen, University of Helsinki, National Institute for Health and Welfare
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  • Ayman H. Fanous, SUNY Downstate Medical Center
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  • Stephen V. Faraone, SUNY Upstate Medical University
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  • Alessia Fiorentino, University College London
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  • Laurent Francioli, Massachusetts General Hospital , Broad Institute of Harvard and MIT
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  • Stacey B. Gabriel, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Diane Gage, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Sarah A. Gagliano Taliun, Université de Montréal, Faculté de Médecine, University of Montreal
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  • Andrea Ganna, University of Helsinki, Massachusetts General Hospital
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  • Giulio Genovese, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • David C. Glahn, Harvard University
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  • Jakob Grove
  • Mei Hua Hall, Harvard University
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  • Eija Hämäläinen, University of Helsinki
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  • Henrike O. Heyne, University of Helsinki, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Matti Holi, University of Helsinki
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  • David M. Hougaard, Statens Serum Institut, Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Daniel P. Howrigan, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Hailiang Huang, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Massachusetts General Hospital
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  • Hai Gwo Hwu, National Taiwan University
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  • René S. Kahn, Icahn School of Medicine at Mount Sinai, VA Medical Center
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  • Hyun Min Kang, University of Michigan, Ann Arbor
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  • Konrad J. Karczewski, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • George Kirov, Cardiff University
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  • James A. Knowles, SUNY Downstate Medical Center
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  • Francis S. Lee, Cornell University
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  • Douglas S. Lehrer, Wright State University
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  • Francesco Lescai, Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Dolores Malaspina, Icahn School of Medicine at Mount Sinai
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  • Stephen R. Marder, Icahn School of Medicine at Mount Sinai
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  • Steven A. McCarroll, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Harvard Medical School, Boston
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  • Andrew M. McIntosh, University of Edinburgh
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  • Helena Medeiros, SUNY Downstate Medical Center
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  • Lili Milani, University of Tartu
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  • Christopher P. Morley, SUNY Upstate Medical University
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  • Derek W. Morris, National University of Ireland, Galway
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  • Preben Bo Mortensen
  • Richard M. Myers, HudsonAlpha Institute for Biotechnology
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  • Merete Nordentoft, University of Copenhagen, Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Niamh L. O’Brien, University College London
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  • Ana Maria Olivares, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Dost Ongur, Harvard University
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  • Willem H. Ouwehand, University of Cambridge
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  • Duncan S. Palmer, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Tiina Paunio, University of Helsinki
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  • Digby Quested, Oxford Health NHS Foundation Trust
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  • Mark H. Rapaport, Emory University
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  • Elliott Rees, Cardiff University
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  • Brandi Rollins, University of California at Irvine
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  • F. Kyle Satterstrom, Stanford University, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Alan Schatzberg, Harvard University
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  • Edward Scolnick, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Laura J. Scott, University of Michigan, Ann Arbor
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  • Sally I. Sharp, University College London
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  • Pamela Sklar, Icahn School of Medicine at Mount Sinai
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  • Jordan W. Smoller, Harvard University
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  • Janet L. Sobell, University of Southern California
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  • Matthew Solomonson, Broad Institute of Harvard and MIT
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  • Eli A. Stahl, Icahn School of Medicine at Mount Sinai
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  • Christine R. Stevens, Broad Institute of Harvard and MIT
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  • Jaana Suvisaari, Finnish Institute for Health and Welfare
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  • Grace Tiao, Broad Institute of Harvard and MIT
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  • Stanley J. Watson, University of Michigan, Ann Arbor
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  • Nicholas A. Watts, Broad Institute of Harvard and MIT
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  • Douglas H. Blackwood, University of Edinburgh
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  • Anders D. Børglum
  • Bruce M. Cohen, Harvard University
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  • Aiden P. Corvin, Trinity College Dublin
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  • Tõnu Esko, University of Tartu
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  • Nelson B. Freimer, Karolinska Institutet
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  • Stephen J. Glatt, SUNY Upstate Medical University
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  • Christina M. Hultman, Johns Hopkins University
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  • Andrew McQuillin, University College London
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  • Aarno Palotie, University of Helsinki, Massachusetts General Hospital , Broad Institute of Harvard and MIT
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  • Carlos N. Pato, SUNY Downstate Medical Center
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  • Michele T. Pato, SUNY Downstate Medical Center
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  • Ann E. Pulver, Johns Hopkins University
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  • David St. Clair, University of Aberdeen
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  • Ming T. Tsuang, University of California
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  • Marquis P. Vawter, University of California at Irvine
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  • James T. Walters, Cardiff University
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  • Thomas M. Werge, University of Copenhagen, Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Roel A. Ophoff, University of California at Los Angeles, Erasmus University Rotterdam
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  • Patrick F. Sullivan, Karolinska Institutet, University of North Carolina
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  • Michael J. Owen, Cardiff University
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  • Michael Boehnke, University of Michigan, Ann Arbor
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  • Michael C. O’Donovan, Cardiff University
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  • Benjamin M. Neale, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • Mark J. Daly, University of Helsinki, Massachusetts General Hospital , The Broad Institute of MIT and Harvard, Cambridge, MA, USA

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 disorders1, epilepsy and severe neurodevelopmental disorders2, 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 risk3, 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.

Original languageEnglish
JournalNature
Volume604
Issue7906
Pages (from-to)509-516
Number of pages8
ISSN0028-0836
DOIs
Publication statusPublished - Apr 2022

    Research areas

  • Exome, Genetic Predisposition to Disease/genetics, Humans, Mutation, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate/genetics, Schizophrenia/genetics

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