Rare nonsynonymous germline and mosaic de novo variants in Japanese patients with schizophrenia.

IF 5 3区 医学 Q1 CLINICAL NEUROLOGY Psychiatry and Clinical Neurosciences Pub Date : 2024-10-22 DOI:10.1111/pcn.13758
Yuichiro Watanabe, Masaki Nishioka, Ryo Morikawa, Satoko Takano-Isozaki, Hirofumi Igeta, Kanako Mori, Tadafumi Kato, Toshiyuki Someya
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Abstract

Aim: Whole-exome sequencing (WES) studies have revealed that germline de novo variants (gDNVs) contribute to the genetic etiology of schizophrenia. However, the contribution of mosaic DNVs (mDNVs) to the risk of schizophrenia remains to be elucidated. In the present study, we systematically investigated the gDNVs and mDMVs that contribute to the genetic etiology of schizophrenia in a Japanese population.

Methods: We performed deep WES (depth: 460×) of 73 affected offspring and WES (depth: 116×) of 134 parents from 67 families with schizophrenia. Prioritized rare nonsynonymous gDNV and mDNV candidates were validated using Sanger sequencing and ultra-deep targeted amplicon sequencing (depth: 71,375×), respectively. Subsequently, we performed a Gene Ontology analysis of the gDNVs and mDNVs to obtain biological insights. Lastly, we selected DNVs in known risk genes for psychiatric and neurodevelopmental disorders.

Results: We identified 62 gDNVs and 98 mDNVs. The Gene Ontology analysis of mDNVs implicated actin filament and actin cytoskeleton as candidate biological pathways. There were eight DNVs in known risk genes: splice region gDNVs in AKAP11 and CUL1; a frameshift gDNV in SHANK1; a missense gDNV in SRCAP; missense mDNVs in CTNNB1, GRIN2A, and TSC2; and a nonsense mDNV in ZFHX4.

Conclusion: Our results suggest the potential contributions of rare nonsynonymous gDNVs and mDNVs to the genetic etiology of schizophrenia. This is the first report of the mDNVs in schizophrenia trios, demonstrating their potential relevance to schizophrenia pathology.

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日本精神分裂症患者中罕见的非同义种系变异和镶嵌式从头变异。
目的:全外显子组测序(WES)研究发现,种系新生变异(gDNVs)是精神分裂症的遗传病因之一。然而,镶嵌型 DNV(mDNV)对精神分裂症风险的贡献仍有待阐明。在本研究中,我们对日本人群中导致精神分裂症遗传病因的gDNVs和mDMVs进行了系统研究:方法:我们对来自 67 个精神分裂症家庭的 73 名受影响后代和 134 名父母进行了深度 WES(深度:460×)研究。使用桑格测序法和超深靶向扩增片段测序法(深度:71375×)分别验证了优先排序的罕见非同义 gDNV 和 mDNV 候选基因。随后,我们对 gDNV 和 mDNV 进行了基因本体分析,以了解其生物学特性。最后,我们在已知的精神和神经发育疾病风险基因中选择了 DNV:我们发现了 62 个 gDNV 和 98 个 mDNV。对 mDNVs 的基因本体分析显示,肌动蛋白丝和肌动蛋白细胞骨架是候选生物通路。已知风险基因中有8个DNV:AKAP11和CUL1中的剪接区gDNV;SHANK1中的移帧gDNV;SRCAP中的错义gDNV;CTNNB1、GRIN2A和TSC2中的错义mDNV;以及ZFHX4中的无义mDNV:我们的研究结果表明,罕见的非同义 gDNVs 和 mDNVs 对精神分裂症的遗传病因有潜在的影响。这是首次报道精神分裂症三联基因中的 mDNVs,表明了它们与精神分裂症病理的潜在相关性。
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来源期刊
CiteScore
7.40
自引率
4.20%
发文量
181
审稿时长
6-12 weeks
期刊介绍: PCN (Psychiatry and Clinical Neurosciences) Publication Frequency: Published 12 online issues a year by JSPN Content Categories: Review Articles Regular Articles Letters to the Editor Peer Review Process: All manuscripts undergo peer review by anonymous reviewers, an Editorial Board Member, and the Editor Publication Criteria: Manuscripts are accepted based on quality, originality, and significance to the readership Authors must confirm that the manuscript has not been published or submitted elsewhere and has been approved by each author
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