Mutation burden of rare variants in schizophrenia candidate genes

PLoS One. 2015 Jun 3;10(6):e0128988. doi: 10.1371/journal.pone.0128988. eCollection 2015.


Background: Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS).

Methods: To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls.

Results: We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • Case-Control Studies
  • E1A-Associated p300 Protein / genetics*
  • Female
  • Gene Expression
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase 14 / genetics*
  • Mutation Rate
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology


  • Nerve Tissue Proteins
  • SHANK3 protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Mitogen-Activated Protein Kinase 14

Grant support

Guy A. Rouleau received financial support through his positions as Canada Research Chair in Genetics of the Nervous System and Jeanne-et-J.-Louis-Levesque Chair for the Genetics of Brain Diseases. Simon L. Girard received financial support from the Fonds de Recherches Québec Santé. All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.