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Rare chromosomal deletions and duplications increase risk of schizophrenia

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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Figure 1: Regions with excess large deletions in cases.

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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.

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

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

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