Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia
Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia
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精神分裂症不一致的同卵双胞胎的全基因组测序表明精神分裂症存在多种遗传风险因素
DOI：
10.1016/j.jgg.2017.05.005
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发表时间：
2017-06-20
影响因子：
5.9
通讯作者：
Chen, Xiaogang
中科院分区：
文献类型：
--
作者：
Tang, Jinsong;Fan, Yu;Chen, Xiaogang
精神分裂症是一种遗传率很高的常见疾病，但其遗传结构仍然难以捉摸。我们对8个精神分裂症单合子(MZ)双生子不一致的家系进行了全基因组测序(WGS)分析，以评估新生突变(DNM)或遗传变异与精神分裂症易感性的潜在关联。双生子共鉴定出8个非同义DNM(包括一个剪接点)，它们要么位于已报道的精神分裂症危险基因(TTN的V24689I突变，GCN1L1的P.S2506T突变，DOCK1的IVS3+1G>；T突变)，要么具有良性到破坏性的效应。通过从三类精神分裂症候选基因中寻找遗传的罕见损伤或功能丧失(LOF)变异和常见的易感等位基因，我们能够提取几个精神分裂症危险基因的遗传变化，包括GAD1，PLXNA2，RELN和FEZ1。在四个家系中分别发现了四个与精神分裂症有关的遗传性拷贝数变异(CNV；包括16p13.11处的大缺失)。大多数家系同时携带错义DNM和遗传性风险变异，这可能表明DNM、遗传的罕见破坏性变异和常见的风险等位基因共同导致精神分裂症的易感性。我们的结果支持精神分裂症是由多种遗传因素的组合引起的，每个DNM/变体显示出相对较小的影响大小。版权所有(C)2017，中国科学院遗传与发育生物学研究所，中国遗传学会。爱思唯尔有限公司和科学出版社出版。版权所有。
Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p. V24689I mutation in TTN, p. S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size. Copyright (C) 2017, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.