2014 Fiscal Year Research-status 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 | The Institute of Physical and Chemical Research |
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Principal Investigator |
SHABEESH BALAN 独立行政法人理化学研究所, 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 | 脳神経疾患 / ゲノム / 遺伝子 / 染色体異常 |
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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. Caused by hemizygous microdeletions at chromosome 22q11.21, about a fourth of the carriers develop schizophrenia. This chromosomal region is considered to be one of the main schizophrenia susceptibility loci, harbouring several candidate genes for disease pathogenesis. The incomplete penetrance of schizophrenia in 22q11.2 deletion suggests polygenic mechanisms that require additional genomic variants outside of the deleted region. This study aimed to decipher the role of genetic defects outside of the 22q11.2 region in increasing the risk for schizophrenia. We performed whole exome sequencing on two individuals with 22q11.2 deletion; one carrier (Person A) with schizophrenia and the other (Person B) who was psychosis-free.
The FISH analysis and aCGH confirmed the 22q11.2 microdeletions, showing a 2.6Mb hemizygous genomic deletion in both participants. The exome sequencing yielded a large number of variants in both participants including the previously reported frameshift mutation in GLO1 in Person A. Based on the specified criteria for variant prioritisation, we identified five heterozygous variants (three frameshift and two nonsense variants) in Person A, which were validated by Sanger sequencing. Interestingly, none of the genes harboring these variants was previously reported to be associated with any neurological or psychiatric phenotypes, and therefore the roles of these genes in manifesting or modulating psychiatric phenotypes warrant future examination.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
染色体22q11.2欠失を持っていて統合失調症を発症したサンプルと、同じ染色体欠失を持ちながら統合失調症を発症していないサンプルを収集することができ、それらサンプルを用いた全エクソーム解析を行い、統合失調症発症に関与する可能性のある３種類のフレームシフト変異と２つのナンセンス変異を同定出来たため。これら５つの遺伝子は、今後の統合失調症や精神疾患のゲノム理解について、重要な情報を提供するものと考えられる。
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| Strategy for Future Research Activity |
上述の５遺伝子のうち、いろいろな過去の文献報告からKAT8遺伝子が精神疾患との関連で最も興味深いと考えられた。
よって今後は、KAT8遺伝子に焦点をあて、精神疾患の大規模サンプルセットによる解析、死後脳における発現解析を進めていく
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[Journal Article] Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.2015
Author(s)
Balan S, Iwayama Y, Yamada K, Toyota T, Ohnishi T, Toyoshima M, Shimamoto C, Ide M, Iwata Y, Suzuki K, Kikuchi M, Hashimoto T, Kanahara N, Yoshikawa T, Maekawa M
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Journal Title
Journal of Neural Transmission
Volume: 122（3）
Pages: 477-485
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Genetic analysis of the glyoxalase system in schizophrenia.2015
Author(s)
Bangel FB, Yamada K, Arai M, Iwayama Y, Balan S, Toyota T, Iwata Y, Suzuki K, Kikuchi M, Hashimoto T, Kanahara N, Mori N, Itokawa M, Stork O, Yoshikawa T
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Journal Title
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Volume: 59
Pages: 105-110
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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