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A polygenic burden of rare disruptive mutations in schizophrenia

Author

Listed:
  • Shaun M. Purcell

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital)

  • Jennifer L. Moran

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Menachem Fromer

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital)

  • Douglas Ruderfer

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Nadia Solovieff

    (Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital)

  • Panos Roussos

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Colm O’Dushlaine

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Kimberly Chambert

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Sarah E. Bergen

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Karolinska Institutet, Stockholm SE-171 77, Sweden)

  • Anna Kähler

    (Karolinska Institutet, Stockholm SE-171 77, Sweden)

  • Laramie Duncan

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Eli Stahl

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Giulio Genovese

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Esperanza Fernández

    (Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium
    VIB Center for Biology of Disease, 3000 Leuven, Belgium)

  • Mark O. Collins

    (Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK)

  • Noboru H. Komiyama

    (Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK)

  • Jyoti S. Choudhary

    (Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK)

  • Patrik K. E. Magnusson

    (Karolinska Institutet, Stockholm SE-171 77, Sweden)

  • Eric Banks

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Khalid Shakir

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Kiran Garimella

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Tim Fennell

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Mark DePristo

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Seth G. N. Grant

    (Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, UK)

  • Stephen J. Haggarty

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
    Harvard Medical School, Massachusetts General Hospital)

  • Stacey Gabriel

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Edward M. Scolnick

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Eric S. Lander

    (Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Christina M. Hultman

    (Karolinska Institutet, Stockholm SE-171 77, Sweden)

  • Patrick F. Sullivan

    (University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA)

  • Steven A. McCarroll

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Pamela Sklar

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai)

Abstract

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Suggested Citation

  • Shaun M. Purcell & Jennifer L. Moran & Menachem Fromer & Douglas Ruderfer & Nadia Solovieff & Panos Roussos & Colm O’Dushlaine & Kimberly Chambert & Sarah E. Bergen & Anna Kähler & Laramie Duncan & El, 2014. "A polygenic burden of rare disruptive mutations in schizophrenia," Nature, Nature, vol. 506(7487), pages 185-190, February.
    • Handle: RePEc:nat:nature:v:506:y:2014:i:7487:d:10.1038_nature12975
    DOI: 10.1038/nature12975
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    Cited by:

    1. Vittoria Mariano & Alexandros K. Kanellopoulos & Giuseppe Aiello & Adrian C. Lo & Eric Legius & Tilmann Achsel & Claudia Bagni, 2023. "SREBP modulates the NADP+/NADPH cycle to control night sleep in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Ralda Nehme & Olli Pietiläinen & Mykyta Artomov & Matthew Tegtmeyer & Vera Valakh & Leevi Lehtonen & Christina Bell & Tarjinder Singh & Aditi Trehan & John Sherwood & Danielle Manning & Emily Peirent , 2022. "The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Yuni Kay & Linda Tsan & Elizabeth A. Davis & Chen Tian & Léa Décarie-Spain & Anastasiia Sadybekov & Anna N. Pushkin & Vsevolod Katritch & Scott E. Kanoski & Bruce E. Herring, 2022. "Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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