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.

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.