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Exome sequencing supports a de novo mutational paradigm for schizophrenia

Abstract

Despite its high heritability, a large fraction of individuals with schizophrenia do not have a family history of the disease (sporadic cases). Here we examined the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exomes of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2, a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region. A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of non-synonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function. Our analyses suggest a major role for de novo mutations in schizophrenia as well as a large mutational target, which together provide a plausible explanation for the high global incidence and persistence of the disease.

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Figure 1: Assessment of the predicted pathogenicity of de novo SNVs identified in schizophrenia cases with respect to protein function.

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References

  1. Gottesman, I.I. & Shields, J. A polygenic theory of schizophrenia. Proc. Natl. Acad. Sci. USA 58, 199–205 (1967).

    Article  CAS  Google Scholar 

  2. 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 

  3. Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Cirulli, E.T. & Goldstein, D.B. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat. Rev. Genet. 11, 415–425 (2010).

    Article  CAS  Google Scholar 

  8. O'Roak, B.J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).

    Article  CAS  Google Scholar 

  9. Vissers, L.E. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010).

    Article  CAS  Google Scholar 

  10. Awadalla, P. et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87, 316–324 (2010).

    Article  CAS  Google Scholar 

  11. Abecasis, G.R. et al. Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. Am. J. Hum. Genet. 74, 403–417 (2004).

    Article  CAS  Google Scholar 

  12. Karayiorgou, M. et al. Phenotypic characterization and genealogical tracing in an Afrikaner schizophrenia database. Am. J. Med. Genet. B Neuropsychiatr. Genet. 124B, 20–28 (2004).

    Article  Google Scholar 

  13. Xu, B. et al. Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proc. Natl. Acad. Sci. USA 106, 16746–16751 (2009).

    Article  Google Scholar 

  14. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  Google Scholar 

  15. Bentley, D.R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).

    Article  CAS  Google Scholar 

  16. 1000 Genomes Project Consortium. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  17. Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. USA 107, 961–968 (2010).

    Article  CAS  Google Scholar 

  18. Li, Y. et al. Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat. Genet. 42, 969–972 (2010).

    Article  CAS  Google Scholar 

  19. Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33 (suppl.), 228–237 (2003).

    Article  CAS  Google Scholar 

  20. Pollard, K.S., Hubisz, M.J., Rosenbloom, K.R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110–121 (2010).

    Article  CAS  Google Scholar 

  21. Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862–864 (1974).

    Article  CAS  Google Scholar 

  22. Kajiwara, K. et al. Cloning of SEZ-12 encoding seizure-related and membrane-bound adhesion protein. Biochem. Biophys. Res. Commun. 222, 144–148 (1996).

    Article  CAS  Google Scholar 

  23. Karayiorgou, M., Simon, T.J. & Gogos, J.A. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat. Rev. Neurosci. 11, 402–416 (2010).

    Article  CAS  Google Scholar 

  24. Bjarnadótttir, T.K. et al. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 84, 23–33 (2004).

    Article  Google Scholar 

  25. Gloriam, D.E., Schioth, H.B. & Fredriksson, R. Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship. Biochim. Biophys. Acta 1722, 235–246 (2005).

    Article  CAS  Google Scholar 

  26. Cruz, M.T. et al. Type 7 adenylyl cyclase is involved in the ethanol and CRF sensitivity of GABAergic synapses in mouse central amygdala. Front. Neurosci. 4, 207 (2011).

    Article  Google Scholar 

  27. Vacic, V. et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499–503 (2011).

    Article  CAS  Google Scholar 

  28. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

  31. Fénelon, K. et al. Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc. Natl. Acad. Sci. USA 108, 4447–4452 (2011).

    Article  Google Scholar 

  32. Sigurdsson, T., Stark, K.L., Karayiorgou, M., Gogos, J.A. & Gordon, J.A. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010).

    Article  CAS  Google Scholar 

  33. Arguello, P.A. & Gogos, J.A. Cognition in mouse models of schizophrenia susceptibility genes. Schizophr. Bull. 36, 289–300 (2010).

    Article  Google Scholar 

  34. Arguello, P.A. & Gogos, J.A. Modeling madness in mice: one piece at a time. Neuron 52, 179–196 (2006).

    Article  CAS  Google Scholar 

  35. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182–189 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the families who participated in this research. We also thank H. Pretorius and nursing sisters R. van Wyk, C. Botha and H. van den Berg for their assistance with subject recruitment, family history assessments and diagnostic evaluations. We thank Y. Sun for technical assistance with DNA extractions and sample preparations and J. Grun for information technology support. We also thank E. Fledderman and S. Thomas for support of the sequencing studies and M. Robinson for critical project support. This work was supported in part by National Institute of Mental Health (NIMH) grants MH061399 (to M.K.) and MH077235 (to J.A.G.) and the Lieber Center for Schizophrenia Research at Columbia University. B.X. was partially supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award.

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Authors and Affiliations

Authors

Contributions

B.X., J.A.G. and M.K. designed the study, interpreted the data and prepared the manuscript. B.X. developed the analysis pipeline and had the primary role in analysis and validation of sequence data. J.L.R. collected the samples and was the primary clinician on the project. S.L. and B.P. performed exome library construction, capture and sequencing. P.D. contributed to the analysis of the data. B.B. contributed to the primary sequence data analysis. S.L. supervised the sequencing project at HudsonAlpha Institute and contributed to the manuscript.

Corresponding authors

Correspondence to Joseph A Gogos or Maria Karayiorgou.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1 and 2. (PDF 2302 kb)

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Xu, B., Roos, J., Dexheimer, P. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet 43, 864–868 (2011). https://doi.org/10.1038/ng.902

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