Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

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 

作者机构：Institute of Mental HealthNational Clinical Research Center for Mental Health Disorders and National Technology Institute of Psychiatryand Key Laboratory of Psychiatry and Mental Health of Hunan ProvinceThe Second Xiangya HospitalCentral South University Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan ProvinceKunming Institute of Zoology Department of PsychiatryThe First Affiliated Hospital of Zhengzhou University Kunming College of Life ScienceUniversity of Chinese Academy of Sciences Neuropsychology and Applied Cognitive Neuroscience Laboratoryand CAS Key Laboratory of Mental HealthInstitute of PsychologyChinese Academy of Sciences Beijing Key Laboratory of Mental DisordersDepartment of PsychiatryBeijing Anding Hospitaland Center of SchizophreniaBeijing Institute for Brain Disorders and Laboratory of Brain Disorders of the Ministry of Science and TechnologyCapital Medical University Unit on Statistical GenomicsIntramural Research ProgramsNational Institute of Mental HealthNIH Institute of Human GeneticsUniversity of Illinois at Chicago Department of PsychiatryThe First Affiliated Hospital of China Medical University CAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of Sciences 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2017年第44卷第6期

页      面：295-306页

核心收录：

学科分类：1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学] 

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) 

主　　题：Whole-genome sequencing Schizophrenia Monozygotic twin De novo mutation Combined effect Susceptibility 

摘      要：Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still *** 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.