| Abstract |
22号染色体q11.2微小缺失传授a high but incomplete risk forschizophrenia. 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). Theschizophreniagroup 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 theschizophreniagroup (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit forschizophreniarisk. 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 idiopathicschizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes. |