Letter | Published:

Rare chromosomal deletions and duplications increase risk of schizophrenia

Nature 455, 237–241 (11 September 2008) | Download Citation

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Abstract

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia2,3,4,5,6,7 and also in neurodevelopmental disorders8,9,10,11, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients12. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

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References

  1. 1.

    , & Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003)

  2. 2.

    et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008)

  3. 3.

    et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465 (2008)

  4. 4.

    et al. Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 571–575 (2006)

  5. 5.

    et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol. Psychiatry 13, 261–266 (2008)

  6. 6.

    et al. DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. Hum. Mol. Genet. 15, 743–749 (2006)

  7. 7.

    et al. Identification of DNA copy-number aberrations by array-comparative genomic hybridization in patients with schizophrenia. Biochem. Biophys. Res. Commun. 344, 531–539 (2006)

  8. 8.

    et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008)

  9. 9.

    et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007)

  10. 10.

    et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

  11. 11.

    & Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006)

  12. 12.

    , & Chromosome 22 deletion syndrome and schizophrenia. Int. Rev. Neurobiol. 73, 1–27 (2006)

  13. 13.

    et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. (in the press)

  14. 14.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)

  15. 15.

    et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms, and rare CNVs. Nature Genet. (in the press)

  16. 16.

    Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998)

  17. 17.

    et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genet. 40, 322–328 (2008)

  18. 18.

    & Schizophrenia, the heteromodal association neocortex and development: potential for a neurogenetic approach. Trends Neurosci. 19, 171–176 (1996)

  19. 19.

    et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995)

  20. 20.

    et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000)

  21. 21.

    , , & Array comparative genomic hybridization (aCGH) analysis in Prader–Willi syndrome. Am. J. Med. Genet. A 146, 854–860 (2008)

  22. 22.

    et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94, 587–592 (1997)

  23. 23.

    et al. Evidence for linkage disequilibrium between the α7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. Am. J. Med. Genet. 105, 669–674 (2001)

  24. 24.

    et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006)

  25. 25.

    , , , & Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 288, 678–682 (2000)

  26. 26.

    et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am. J. Hum. Genet. 68, 661–673 (2001)

  27. 27.

    & Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002)

  28. 28.

    et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res. 17, 482–491 (2007)

  29. 29.

    , & DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007)

  30. 30.

    et al. Large recurrent microdeletions associated with schizophrenia. Nature doi: 10.1038/nature07229 (this issue)

  31. 31.

    DSM-IV. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, 2000)

  32. 32.

    ICD-10. International Statistical Classification of Diseases and Related Health Problems 10th revision (World Health Organization, 2007)

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Acknowledgements

We thank the patients and families who contributed their time and DNA to these studies, and also D. Altshuler and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion. The group at the Stanley Center for Psychiatric Research at the Broad Institute was supported by the Stanley Medical Research Institute (E.M.S.), the Sylvan C. Herman Foundation (E.M.S.), and MH071681 (P.S.). The Cardiff University group was supported by a Medical Research Council (UK) Programme grant and the National Institutes of Mental Health (USA) (CONTE: 2 P50 MH066392-05A1). The group at Karolinska Institutet was supported by the Swedish Council for Working Life and Social Research (FO 184/2000; 2001-2368). The Massachusetts General Hospital group was supported by the Stanley Medical Research Institute (P.S.), MH071681 (P.S.) and a Narsad Young Investigator Award (S.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council. The Trinity College Dublin group was supported by Science Foundation Ireland, the Health Research Board (Ireland), the Stanley Medical Research Institute and the Wellcome Trust; Irish controls were supplied by J. McPartlin from the Trinity College Biobank. The work at the University of Aberdeen was partly funded by GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. The University College London clinical and control samples were collected with support from the Neuroscience Research Charitable Trust, the Camden and Islington Mental Health and Social Care Trust, East London and City Mental Heath Trust, the West Berkshire NHS Trust, the West London Mental Health Trust, Oxfordshire and Buckinghamshire Mental Health Partnership NHS Trust, South Essex Partnership NHS Foundation Trust, Gloucestershire Partnership NHS Foundation Trust, Mersey Care NHS Trust, Hampshire Partnership NHS Trust and the North East London Mental Health Trust. The collection of the University of Edinburgh cohort was supported by grants from the Wellcome Trust, London, and the Chief Scientist Office of the Scottish Executive. The group at the University of North Carolina, Chapel Hill, was supported by MH074027, MH077139 and MH080403, the Sylvan C. Herman Foundation (P.F.S.) and the Stanley Medical Research Institute (P.F.S.) The group at the University of Southern California thanks the patients and their families for their collaboration, and acknowledges the support of the National Institutes of Mental Health and the Department of Veterans Affairs.

Author information

    • Digby Quested

    Present address: Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.

Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Jennifer L. Stone
    • , Douglas M. Ruderfer
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Shaun M. Purcell
    •  & Pamela Sklar (Leader)

  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Jennifer L. Stone
    • , Douglas M. Ruderfer
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Mark J. Daly
    • , Shaun M. Purcell
    • , Edward M. Scolnick
    • , Pamela Sklar (Leader)
    • , Mark Daly
    •  & Kimberly Chambert

  3. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

    • Jennifer L. Stone
    • , Douglas M. Ruderfer
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Joshua Korn
    • , Mark J. Daly
    • , Shaun M. Purcell
    • , Edward M. Scolnick
    • , Pamela Sklar (Leader)
    • , Steve A. McCarroll
    • , Mark Daly
    • , Kimberly Chambert
    • , Casey Gates
    • , Stacey B. Gabriel
    • , Scott Mahon
    •  & Kristen Ardlie

  4. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Jennifer L. Stone
    • , Douglas M. Ruderfer
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Joshua Korn
    • , Mark J. Daly
    • , Shaun M. Purcell
    • , Pamela Sklar (Leader)
    • , Steve A. McCarroll
    •  & Mark Daly

  5. School of Medicine, Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.

    • Michael C. O’Donovan
    • , George K. Kirov
    • , Nick J. Craddock
    • , Michael J. Owen
    • , Peter A. Holmans
    • , Nigel M. Williams
    • , Lucy Georgieva
    • , Ivan Nikolov
    • , N. Norton
    •  & H. Williams

  6. Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.

    • Hugh Gurling
    • , Andrew McQuillin
    • , Khalid Choudhury
    • , Susmita Datta
    • , Jonathan Pimm
    • , Vinay Puri
    • , Robert Krasucki
    • , Jacob Lawrence
    •  & Nicholas Bass

  7. Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh EH10 5HF, UK.

    • Douglas H. R. Blackwood
    • , Walter J. Muir
    • , Kevin A. McGhee
    • , Ben Pickard
    • , Pat Malloy
    • , Alan W. Maclean
    •  & Margaret Van Beck

  8. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.

    • Aiden Corvin
    • , Michael Gill
    • , Derek W. Morris
    • , Colm T. O’Dushlaine
    •  & Elaine Kenny

  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

    • Christina M. Hultman
    • , Paul Lichtenstein
    •  & Emma F. Thelander

  10. Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.

    • Christina M. Hultman

  11. Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.

    • Carlos N. Pato
    • , Michele T. Pato
    • , Helena Medeiros
    • , Celia Carvalho
    • , Ayman Fanous
    • , David Conti
    •  & James A. Knowles

  12. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.

    • David St Clair
    •  & Soh Leh Kwan

  13. Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Patrick F. Sullivan
    •  & Patrick Sullivan

  14. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.

    • Stuart Macgregor
    •  & Peter M. Visscher

  15. Department of Medical Genetics, University Hospital Maichin Dom, Sofia 1431, Bulgaria.

    • Draga Toncheva

  16. Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia 1431, Bulgaria.

    • Vihra Milanova

  17. Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

    • John L. Waddington

  18. West Berkshire NHS Trust, 25 Erleigh Road, Reading RG3 5LR, UK.

    • Srinivasa Thirumalai

  19. West London Mental Health Trust, Hammersmith and Fulham Mental Health Unit and St Bernard’s Hospital, London W6 8RF, UK.

    • Digby Quested

  20. Queen Mary College, University of London and East London and City Mental Health Trust, Royal London Hospital, Whitechapel, London E1 1BB, UK.

    • David Curtis

  21. Department of Mental Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.

    • Caroline Crombie
    •  & Gillian Fraser

  22. Ravenscraig Hospital, Inverkip Road, Greenock PA16 9HA, UK.

    • Nicholas Walker

  23. State University of New York – Upstate Medical University, Syracuse, New York 13210, USA.

    • Frank Middleton
    •  & Christopher Morley

  24. Washington VA Medical Center, Washington, DC 20422, USA.

  25. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC 20057, USA.

  26. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.

  27. Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.

    • Carlos Paz Ferreira

  28. Department of Psychiatry, University of Coimbra, 3004-504 Coimbra, Portugal.

    • Antonio Macedo
    •  & M. Helena Azevedo

Consortia

  1. The International Schizophrenia Consortium

    Manuscript preparation

    Data analysis

    Management committee

    Cardiff University

    Karolinska Institutet/University of North Carolina at Chapel Hill

    Trinity College Dublin

    University College London

    University of Aberdeen

    University of Edinburgh

    Queensland Institute of Medical Research

    University of Southern California

    Massachusetts General Hospital

    Stanley Center for Psychiatric Research and Broad Institute of MIT and Harvard

Authors

    Corresponding authors

    Correspondence to Pamela Sklar or Pamela Sklar or Pamela Sklar or Pamela Sklar.

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      The file contains Supplementary Notes, Supplementary Tables S1-S12, Supplementary Figures 1-2 and additional references.

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    DOI

    https://doi.org/10.1038/nature07239

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