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Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia 被引量：6

Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia
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摘要 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.V24689 I mutation in TTN, p.S2506 T 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. 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.V24689 I mutation in TTN, p.S2506 T 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.
作者 Jinsong Tang Yu Fan Hong Li Qun Xiang Deng-Feng Zhang Zongchang Li Ying He Yanhui Liao Ya Wang Fan He Fengyu Zhang Yin Yao Shugart Chunyu Liu Yanqing Tang Raymond C.K.Chan Chuan-Yue Wang Yong-Gang Yao Xiaogang Chen
机构地区 Institute of Mental Health Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province Department of Psychiatry Kunming College of Life Science Neuropsychology and Applied Cognitive Neuroscience Laboratory Beijing Key Laboratory of Mental Disorders Unit on Statistical Genomics Institute of Human Genetics Department of Psychiatry CAS Center for Excellence in Brain Science and Intelligence Technology
出处 《Journal of Genetics and Genomics》 SCIE CAS CSCD 2017年第6期295-306,共12页 遗传学报（英文版）
基金 supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 and XDB02030002) the Bureau of Frontier Sciences and Education,Chinese Academy of Sciences (QYZDJ-SSW-SMC005) the National Natural Science Foundation of China (Nos. 81088001,81271484,81471361 and 81371480) the Beijing Training Project for the Leading Talents in S & T (Z151100000315020) the National Key Basic Research and Development Program (973) (2012CB517904) the CAS/SAFEA International Partnership Programme for Creative Research Teams (Y2CX131003)
关键词 Whole-genome sequencing SCHIZOPHRENIA Monozygotic twin De novo mutation Combined effect SUSCEPTIBILITY Whole-genome sequencing Schizophrenia Monozygotic twin De novo mutation Combined effect Susceptibility
分类号 R749.3 [医药卫生—神经病学与精神病学]
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Journal of Genetics and Genomics
2017年 第6期

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