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Copy-number variations associated with neuropsychiatric conditions

Abstract

Neuropsychiatric conditions such as autism and schizophrenia have long been attributed to genetic alterations, but identifying the genes responsible has proved challenging. Microarray experiments have now revealed abundant copy-number variation — a type of variation in which stretches of DNA are duplicated, deleted and sometimes rearranged — in the human population. Genes affected by copy-number variation are good candidates for research into disease susceptibility. The complexity of neuropsychiatric genetics, however, dictates that assessment of the biomedical relevance of copy-number variants and the genes that they affect needs to be considered in an integrated context.

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Figure 1: Model of the relative contribution of CNVs in susceptibility to ASD.
Figure 2: Assessing the relevance of CNV.

References

  1. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004).

    CAS  Article  PubMed  Google Scholar 

  2. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  ADS  Article  PubMed  Google Scholar 

  3. Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nature Rev. Genet. 7, 85–97 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006). This paper provides the first comprehensive CNV map of the human genome, describing the ubiquity and role of this form of variation in genetic diversity.

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  5. Lupski, J. R. & Stankiewicz, P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 1, e49 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  6. van Ommen, G. J. Frequency of new copy number variation in humans. Nature Genet. 37, 333–334 (2005).

    CAS  Article  PubMed  Google Scholar 

  7. Lupski, J. R. Genomic rearrangements and sporadic disease. Nature Genet. 39, S43–S47 (2007).

    CAS  Article  PubMed  Google Scholar 

  8. Emerson, J. J., Cardoso-Moreira, M., Borevitz, J. O. & Long, M. Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster . Science 320, 1629–1631 (2008).

    CAS  ADS  Article  PubMed  Google Scholar 

  9. Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).

    CAS  Article  PubMed  Google Scholar 

  10. Buchanan, J. A. & Scherer, S. W. Contemplating effects of genomic structural variation. Genet. Med. 10, 639–647 (2008).

    Article  PubMed  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).

    CAS  Article  PubMed  Google Scholar 

  12. Inoue, K. & Lupski, J. R. Genetics and genomics of behavioral and psychiatric disorders. Curr. Opin. Genet. Dev. 13, 303–309 (2003).

    CAS  Article  PubMed  Google Scholar 

  13. Burmeister, M., McInnis, M. G. & Zollner, S. Psychiatric genetics: progress amid controversy. Nature Rev. Genet. 9, 527–540 (2008).

    CAS  Article  PubMed  Google Scholar 

  14. Veenstra-Vanderweele, J., Christian, S. L. & Cook, E. H. Jr. Autism as a paradigmatic complex genetic disorder. Annu. Rev. Genomics Hum. Genet. 5, 379–405 (2004).

    CAS  Article  PubMed  Google Scholar 

  15. Abrahams, B. S. & Geschwind, D. H. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341–355 (2008).

    CAS  Article  PubMed  Google Scholar 

  16. Turner, D. J. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nature Genet. 40, 90–95 (2008).

    CAS  Article  PubMed  Google Scholar 

  17. Berg, J. S. et al. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams–Beuren syndrome region. Genet. Med. 9, 427–441 (2007).

    Article  PubMed  Google Scholar 

  18. Cook, E. H. Jr et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60, 928–934 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007). This important study found a higher proportion of de novo CNVs in simplex autism families than in multiplex autism families, suggesting that the underlying genetic mechanisms of disease may be distinct in these cases.

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  20. Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007). This comprehensive study of linkage and CNVs delineates the importance of genetic and phenotypic heterogeneity in autism, as well as how CNVs can be used to stratify cohorts.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  23. Kumar, R. A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008).

    CAS  Article  PubMed  Google Scholar 

  24. Christian, S. L. et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol. Psychiatry 63, 1111–1117 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Jacquemont, M. L. et al. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J. Med. Genet. 43, 843–849 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008).

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  ADS  Article  PubMed  Google Scholar 

  28. Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008).

    CAS  Article  PubMed  Google Scholar 

  29. The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).

  30. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008). This novel study exploited rare recurrent CNVs discovered to be under negative selection through population genetic studies and applied this information to identify schizophrenia-susceptibility loci.

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  31. de Vries, B. B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  Article  PubMed  Google Scholar 

  33. Mefford, H. C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. doi:10.1056/NEJMoa0805384; published online 10 September 2008.

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

    CAS  Article  PubMed  Google Scholar 

  35. Miller, D. T. et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J. Med. Genet. doi:10.1136/jmg.2008.059907; published online 19 September 2008.

  36. Tabor, H. K. & Cho, M. K. Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research. Genet. Med. 9, 626–631 (2007). This paper provides a thorough discussion of the relevance of CNV data in complex disease studies, including ethical considerations arising in this new field.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  38. Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2007).

    CAS  Article  PubMed  Google Scholar 

  39. Bruder, C. E. et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am. J. Hum. Genet. 82, 763–771 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Zhao, X. et al. A unified genetic theory for sporadic and inherited autism. Proc. Natl Acad. Sci. USA 104, 12831–12836 (2007).

    CAS  ADS  Article  PubMed  PubMed Central  Google Scholar 

  41. Beaudet, A. L. Autism: highly heritable but not inherited. Nature Med. 13, 534–536 (2007).

    CAS  Article  PubMed  Google Scholar 

  42. Darilek, S. et al. Pre- and postnatal genetic testing by array-comparative genomic hybridization: genetic counseling perspectives. Genet. Med. 10, 13–18 (2008).

    CAS  Article  PubMed  Google Scholar 

  43. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 9, 356–369 (2008).

    CAS  Article  PubMed  Google Scholar 

  44. Scherer, S. W. et al. Challenges and standards in integrating surveys of structural variation. Nature Genet. 39, S7–S15 (2007).

    CAS  Article  PubMed  Google Scholar 

  45. De Luca, A. et al. Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification. J. Med. Genet. 44, 800–808 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Grisart, B. et al. NF1 microduplication first clinical report: association with mild mental retardation, early onset of baldness and dental enamel hypoplasia? Eur. J. Hum. Genet. 16, 305–311 (2008).

    CAS  Article  PubMed  Google Scholar 

  47. 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).

    CAS  Article  PubMed  Google Scholar 

  48. Lachman, H. M. et al. Increase in GSK3β gene copy number variation in bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144, 259–265 (2007).

    Article  Google Scholar 

  49. Chartier-Harlin, M. C. et al. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).

    CAS  Article  PubMed  Google Scholar 

  50. Ibanez, P. et al. Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169–1171 (2004).

    CAS  Article  PubMed  Google Scholar 

  51. Shelley, B. P., Robertson, M. M. & Turk, J. An individual with Gilles de la Tourette syndrome and Smith–Magenis microdeletion syndrome: is chromosome 17p11.2 a candidate region for Tourette syndrome putative susceptibility genes? J. Intellect. Disabil. Res. 51, 620–624 (2007).

    CAS  Article  PubMed  Google Scholar 

  52. Lawson-Yuen, A., Saldivar, J. S., Sommer, S. & Picker, J. Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur. J. Hum. Genet. 16, 614–618 (2008).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank P. Szatmari, R. Weksberg, C. Marshall, L. Feuk and D. Pinto for ideas. Research in our laboratories is supported by The Centre for Applied Genomics, Genome Canada–Ontario Genomics Institute, the Canadian Institutes for Health Research (CIHR), the Canadian Institute for Advanced Research, the McLaughlin Centre for Molecular Medicine, the Canadian Foundation for Innovation, the Ontario Ministry of Research & Innovation, the National Institutes of Health (grant number HD055751, to E.H.C.), Children's Brain Research Foundation, Jean Young and Walden W. Shaw Foundation, Autism Speaks, and the SickKids Foundation. S.W.S. holds the GlaxoSmithKline–CIHR Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children.

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Correspondence should be addressed to S.W.S. (steve@genet.sickkids.on.ca).

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Cook Jr, E., Scherer, S. Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923 (2008). https://doi.org/10.1038/nature07458

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