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. Access through your institution Buy or subscribe This is a preview of subscription

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  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Department of Psychiatry, Columbia University, New York, New York, USA Bin Xu & Maria Karayiorgou * Department of Physiology & Cellular Biophysics, Columbia University, New York, New

York, USA Bin Xu & Joseph A Gogos * Weskoppies Hospital & Department of Psychiatry, University of Pretoria, Pretoria, South Africa J Louw Roos * HudsonAlpha Institute for

Biotechnology, Huntsville, Alabama, USA Phillip Dexheimer, Braden Boone, Brooks Plummer & Shawn Levy * Department of Neuroscience, Columbia University, New York, New York, USA Joseph A

Gogos Authors * Bin Xu View author publications You can also search for this author inPubMed Google Scholar * J Louw Roos View author publications You can also search for this author

inPubMed Google Scholar * Phillip Dexheimer View author publications You can also search for this author inPubMed Google Scholar * Braden Boone View author publications You can also search

for this author inPubMed Google Scholar * Brooks Plummer View author publications You can also search for this author inPubMed Google Scholar * Shawn Levy View author publications You can

also search for this author inPubMed Google Scholar * Joseph A Gogos View author publications You can also search for this author inPubMed Google Scholar * Maria Karayiorgou View author

publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Note, Supplementary Figures 1–4 and Supplementary

Tables 1 and 2. (PDF 2302 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 26 May 2011 * Accepted: 12 July 2011 * Published: 07

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