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. 2011 Aug 7;43(9):864-8.
doi: 10.1038/ng.902.

Exome Sequencing Supports a De Novo Mutational Paradigm for Schizophrenia

Free PMC article

Exome Sequencing Supports a De Novo Mutational Paradigm for Schizophrenia

Bin Xu et al. Nat Genet. .
Free PMC article


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.

Conflict of interest statement


The authors declare no competing financial interests.


Figure 1
Figure 1. The potential of de novo SNVs in cases to affect protein function
Comparison of the distribution of phyloP scores (which depend on the evolutionary conservation of affected nucleotides) (A) and Grantham scores (which depend on the properties of the changed residue) (B) among de novo mutations and private inherited variants in SCZ cases.

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    1. Gottesman II, Shields J. A polygenic theory of schizophrenia. Proc Natl Acad Sci U S A. 1967;58:199–205. - PMC - PubMed
    1. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–92. - PubMed
    1. Lichtenstein P, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373:234–9. - PMC - PubMed
    1. Lupski JR. Genomic rearrangements and sporadic disease. Nat Genet. 2007;39:S43–7. - PubMed
    1. Karayiorgou M, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92:7612–6. - PMC - PubMed

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