Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome
| Autor: | Bhooma Thiruvahindrapuram, Stephen W. Scherer, Brendan J. Frey, Daniele Merico, Christian R. Marshall, Thomas Nalpathamkalam, Gregory Costain, Babak Alipanahi, Eva W.C. Chow, Mehdi Zarrei, Nancy J. Butcher, Danielle M. Andrade, Lucas Ogura, Matthew J. Gazzellone, Anne S. Bassett |
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| Rok vydání: | 2015 |
| Předmět: |
Male
BSN MYH9 0302 clinical medicine synapse DiGeorge syndrome Copy-number variation FMR1 Genetics (clinical) DIP2A Genetics 0303 health sciences microRNA ABLIM1 Neuron projection copy number variation RNA-Binding Proteins Middle Aged connectivity lincRNA Female RNA Long Noncoding Haploinsufficiency SLITRK2 Adult Adolescent Schizophrenia (object-oriented programming) MYH10 EXOC4 Investigations Biology noncoding RNA ZDHHC5 DGCR8 03 medical and health sciences 22q11 Deletion Syndrome Genetic model DiGeorge Syndrome medicine Humans Molecular Biology 030304 developmental biology 22q11 deletion syndrome PTPRG Genome Human medicine.disease genetic architecture schizophrenia ITM2C postsynaptic density PCNT Case-Control Studies polygenic risk score next-generation sequencing Human genome 030217 neurology & neurosurgery |
| Zdroj: | G3: Genes|Genomes|Genetics |
| ISSN: | 2160-1836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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