Rare chromosomal deletions and duplications increase risk of schizophrenia (original) (raw)

References

  1. Sullivan, P. F., Kendler, K. S. & Neale, M. C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003)
    Article Google Scholar
  2. Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008)
    Article CAS ADS Google Scholar
  3. Kirov, G. et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465 (2008)
    Article CAS Google Scholar
  4. Flomen, R. H. 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)
    Article Google Scholar
  5. Friedman, J. I. et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol. Psychiatry 13, 261–266 (2008)
    Article CAS Google Scholar
  6. Wilson, G. M. 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)
    Article CAS Google Scholar
  7. Moon, H. J. 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)
    Article CAS Google Scholar
  8. Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008)
    Article CAS Google Scholar
  9. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007)
    Article CAS ADS Google Scholar
  10. Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)
    Article CAS Google Scholar
  11. Lee, J. A. & Lupski, J. R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006)
    Article CAS Google Scholar
  12. Williams, N. M., O’Donovan, M. C. & Owen, M. J. Chromosome 22 deletion syndrome and schizophrenia. Int. Rev. Neurobiol. 73, 1–27 (2006)
    Article CAS Google Scholar
  13. McCarroll, S. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. (in the press)
  14. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)
    Article CAS Google Scholar
  15. Korn, J. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms, and rare CNVs. Nature Genet. (in the press)
  16. Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998)
    Article CAS Google Scholar
  17. Sharp, A. J. et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genet. 40, 322–328 (2008)
    Article CAS Google Scholar
  18. Ross, C. A. & Pearlson, G. D. Schizophrenia, the heteromodal association neocortex and development: potential for a neurogenetic approach. Trends Neurosci. 19, 171–176 (1996)
    Article CAS Google Scholar
  19. Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995)
    Article CAS ADS Google Scholar
  20. Shaikh, T. H. 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)
    Article CAS Google Scholar
  21. Butler, M. G., Fischer, W., Kibiryeva, N. & Bittel, D. C. Array comparative genomic hybridization (aCGH) analysis in Prader–Willi syndrome. Am. J. Med. Genet. A 146, 854–860 (2008)
    Article Google Scholar
  22. Freedman, R. et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94, 587–592 (1997)
    Article CAS ADS Google Scholar
  23. Xu, J. 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)
    Article CAS Google Scholar
  24. Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006)
    Article CAS Google Scholar
  25. Brzustowicz, L. M., Hodgkinson, K. A., Chow, E. W., Honer, W. G. & Bassett, A. S. Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 288, 678–682 (2000)
    Article CAS ADS Google Scholar
  26. Gurling, H. M. 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)
    Article CAS Google Scholar
  27. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002)
    Article CAS Google Scholar
  28. Shaikh, T. H. et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res. 17, 482–491 (2007)
    Article CAS Google Scholar
  29. Lee, J. A., Carvalho, C. M. & Lupski, J. R. A. DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007)
    Article CAS Google Scholar
  30. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature doi: 10.1038/nature07229 (this issue)
  31. DSM-IV. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, 2000)
  32. ICD-10. International Statistical Classification of Diseases and Related Health Problems 10th revision (World Health Organization, 2007)

Download references

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

Author notes

  1. Lists of members and affiliations appear at the end of the paper.
  2. Washington VA Medical Center, Washington, DC 20422, USA.
  3. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC 20057, USA.
  4. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.

Authors and 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), Jennifer L. Stone, Douglas M. Ruderfer, Pamela Sklar, Shaun M. Purcell (Leader), Shaun M. Purcell, Jennifer L. Stone, Pamela Sklar (Leader), Jennifer L. Stone, Douglas M. Ruderfer, Shaun M. Purcell, Pamela Sklar, Shaun M. Purcell, Jennifer L. Stone, Douglas M. Ruderfer & Pamela Sklar
  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), Jennifer L. Stone, Douglas M. Ruderfer, Mark J. Daly, Pamela Sklar, Shaun M. Purcell (Leader), Shaun M. Purcell, Edward M. Scolnick, Jennifer L. Stone, Pamela Sklar (Leader), Jennifer L. Stone, Douglas M. Ruderfer, Mark Daly, Shaun M. Purcell, Pamela Sklar, Shaun M. Purcell, Jennifer L. Stone, Kimberly Chambert, Douglas M. Ruderfer, Mark J. Daly, Edward M. Scolnick & Pamela Sklar
  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), Jennifer L. Stone, Douglas M. Ruderfer, Joshua Korn, Mark J. Daly, Pamela Sklar, Shaun M. Purcell (Leader), Shaun M. Purcell, Edward M. Scolnick, Jennifer L. Stone, Pamela Sklar (Leader), Jennifer L. Stone, Douglas M. Ruderfer, Joshua Korn, Steve A. McCarroll, Mark Daly, Shaun M. Purcell, Pamela Sklar, Shaun M. Purcell, Jennifer L. Stone, Kimberly Chambert, Douglas M. Ruderfer, Joshua Korn, Steve A. McCarroll, Casey Gates, Stacey B. Gabriel, Scott Mahon, Kristen Ardlie, Mark J. Daly, Edward M. Scolnick & Pamela Sklar
  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), Jennifer L. Stone, Douglas M. Ruderfer, Joshua Korn, Mark J. Daly, Pamela Sklar, Shaun M. Purcell (Leader), Shaun M. Purcell, Jennifer L. Stone, Pamela Sklar (Leader), Jennifer L. Stone, Douglas M. Ruderfer, Joshua Korn, Steve A. McCarroll, Mark Daly, Shaun M. Purcell, Pamela Sklar, Shaun M. Purcell, Jennifer L. Stone, Douglas M. Ruderfer, Joshua Korn, Steve A. McCarroll, Mark J. Daly & Pamela Sklar
  5. Department of Psychological Medicine, School of Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.,
    Michael C. O’Donovan, George K. Kirov, Nick J. Craddock, Michael J. Owen, George K. Kirov, Peter A. Holmans, Michael C. O’Donovan, Nick J. Craddock, George K. Kirov, Michael C. O’Donovan, Michael J. Owen, Michael C. O’Donovan, George K. Kirov, Nick J. Craddock, Peter A. Holmans, Nigel M. Williams, Lucy Georgieva, Ivan Nikolov, N. Norton, H. Williams & Michael J. Owen
  6. Department of Mental Health Sciences, Molecular Psychiatry Laboratory, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.,
    Hugh Gurling, Andrew McQuillin, Andrew McQuillin, Hugh Gurling, Andrew McQuillin, Andrew McQuillin, Khalid Choudhury, Susmita Datta, Jonathan Pimm, Vinay Puri, Robert Krasucki, Jacob Lawrence, Nicholas Bass & Hugh Gurling
  7. Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh EH10 5HF, UK.,
    Douglas H. R. Blackwood, Douglas H. R. Blackwood, Douglas H. R. Blackwood, Walter J. Muir, Kevin A. McGhee, Ben Pickard, Pat Malloy, Alan W. Maclean & Margaret Van Beck
  8. Department of Psychiatry and Institute of Molecular Medicine, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin 2, Ireland.,
    Aiden Corvin, Michael Gill, Derek W. Morris, Colm T. O’Dushlaine, Aiden Corvin, Michael Gill, Derek W. Morris, Colm T. O’Dushlaine, Elaine Kenny, Michael Gill & Aiden Corvin
  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.,
    Christina M. Hultman, Paul Lichtenstein, Christina M. Hultman, Paul Lichtenstein, Christina M. Hultman, Paul Lichtenstein & Emma F. Thelander
  10. Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.,
    Christina M. Hultman, Christina M. Hultman & Christina M. Hultman
  11. Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.,
    Carlos N. Pato, Carlos N. Pato, Michele T. Pato, Helena Medeiros, Celia Carvalho, Ayman Fanous, David Conti, James A. Knowles & Carlos N. Pato
  12. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.,
    David St Clair, David St Clair, Soh Leh Kwan & David St Clair
  13. Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,
    Patrick F. Sullivan, Patrick F. Sullivan, Patrick F. Sullivan & Patrick Sullivan
  14. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.,
    Stuart Macgregor, Peter M. Visscher, Peter M. Visscher & Stuart Macgregor
  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. Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.,
    Carlos Paz Ferreira
  25. Department of Psychiatry, University of Coimbra, 3004-504 Coimbra, Portugal.,
    Antonio Macedo & M. Helena Azevedo

Consortia

The International Schizophrenia Consortium

Corresponding authors

Correspondence toPamela Sklar, Pamela Sklar, Pamela Sklar or Pamela Sklar.

Supplementary information

Supplementary Information 1

The file contains Supplementary Notes, Supplementary Tables S1-S12, Supplementary Figures 1-2 and additional references. (PDF 469 kb)

PowerPoint slides

Rights and permissions

About this article

Cite this article

The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia.Nature 455, 237–241 (2008). https://doi.org/10.1038/nature07239

Download citation