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Exome sequencing supports a de novo mutational paradigm for schizophrenia


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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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



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).

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