2015 Fiscal Year Annual Research Report
Additional genetic defects outside commonly deleted region in 22q11.2 deletion with psychosis; a prospect for identifying novel schizophrenia candidate genes
| Project/Area Number |
26860954
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
SHABEESH BALAN 国立研究開発法人理化学研究所, 脳科学総合研究センター, 研究員 (70721588)
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| Project Period (FY) |
2014-04-01 – 2016-03-31
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| Keywords | 22q11.2 deletion / Schizophrenia / SNX31 / CLV2 / EFCAB11 / KAT8 / APOH |
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| Outline of Annual Research Achievements |
Among structural variants, 22q11.2 deletion is one of the highest risk factors for developing schizophrenia, as this chromosomal region harbors several candidate genes for the disease pathogenesis. Approximately 1/4th of the 22q11.2 deletion subjects only develop schizophrenia. This incomplete penetrance of schizophrenia in 22q11.2 deletion suggests polygenic mechanisms that require additional genomic variants outside the deleted region. This study aimed to decipher the role of genetic defects outside the 22q11.2 region in increasing the risk for schizophrenia. We performed whole exome sequencing on two subjects with 22q11.2 deletions; one with schizophrenia and the second psychosis free. Based on the stringent criteria for variant prioritization, we identified 5 heterozygous variants in genes (3 frameshift: KAT8, APOH and SNX31 and 2 nonsense variants: EFCAB11 and CLVS2 ) outside the deletion region in the 22q11.2 deletion patient with schizophrenia. Interestingly, none of the genes harboring these variants were previously reported to be associated with any neurological or psychiatric phenotypes, though they were relevant for neuronal function. No novel mutations in the 22q11.2-hemizygous region were observed in 22q11.2 deletion patient with schizophrenia. The novel genetic variants related to neuronal function exclusively in the patient with schizophrenia will pave the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia. The role of these genes in manifesting/modulating psychiatric phenotypes warrant future examination.
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