Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome

G3 (Bethesda). 2015 Sep 16;5(11):2453-61. doi: 10.1534/g3.115.021345.


Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.

Keywords: 22q11 deletion syndrome; ABLIM1; BSN; DGCR8; DIP2A; EXOC4; FMR1; ITM2C; MYH10; MYH9; PCNT; PTPRG; SLITRK2; ZDHHC5; connectivity; copy number variation; genetic architecture; lincRNA; microRNA; next-generation sequencing; noncoding RNA; polygenic risk score; postsynaptic density; schizophrenia; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • DiGeorge Syndrome / complications*
  • DiGeorge Syndrome / genetics
  • Female
  • Genome, Human*
  • Humans
  • Male
  • Middle Aged
  • RNA, Long Noncoding / genetics
  • RNA-Binding Proteins / genetics
  • Schizophrenia / epidemiology
  • Schizophrenia / genetics*


  • DGCR8 protein, human
  • RNA, Long Noncoding
  • RNA-Binding Proteins