De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia

Nat Genet. 2012 Dec;44(12):1365-9. doi: 10.1038/ng.2446. Epub 2012 Oct 3.


To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structures and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of de novo nonsynonymous single-nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, which is unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles, but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the genomic and neural architecture of schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Autophagy-Related Proteins
  • Base Sequence
  • Brain / growth & development
  • Cohort Studies
  • Dihydrouracil Dehydrogenase (NADP) / genetics
  • Exome / genetics
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Laminin / genetics
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Neurons / physiology*
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Schizophrenia / genetics*
  • Sequence Analysis, DNA
  • South Africa
  • United States
  • Vesicular Transport Proteins / genetics
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Intracellular Signaling Peptides and Proteins
  • Laminin
  • Nuclear Proteins
  • VPS39 protein, human
  • Vesicular Transport Proteins
  • laminin alpha 2
  • transformation-transcription domain-associated protein
  • Dihydrouracil Dehydrogenase (NADP)