Strategic Priority Research Program of the Chinese Academy of Sciences(XDB02020003
; Bureau of Frontier Sciences and Education, Chinese Academy of Sciences(QYZDJ-SSW-SMC005)
; National Natural Science Foundation of China(81088001
; Beijing Training Project for the Leading Talents in S T(Z151100000315020)
; National Key Basic Research and Development Program (973)(2012CB517904)
; CAS/SAFEA International Partnership Programme for Creative Research Teams(Y2CX131003)
; XDB02030002)
; 81271484
; 81471361
; 81371480)
英文摘要:
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. 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.
1.Cent S Univ, Natl Clin Res Ctr Mental Hlth Disorders, Inst Mental Hlth, Xiangya Hosp 2, Changsha 410011, Hunan, Peoples R China 2.Cent S Univ, Xiangya Hosp 2, Natl Technol Inst Psychiat, Changsha 410011, Hunan, Peoples R China 3.Cent S Univ, Xiangya Hosp 2, Key Lab Psychiat & Mental Hlth Hunan Prov, Changsha 410011, Hunan, Peoples R China 4.Chinese Acad Sci & Yunnan Prov, Key Lab Anim Models & Human Dis Mech, Kunming Inst Zool, Kunming 650223, Peoples R China 5.Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming 650204, Peoples R China 6.Chinese Acad Sci, Neuropsychol & Appl Cognit Neurosci Lab, Inst Psychol, Beijing 100101, Peoples R China 7.Chinese Acad Sci, CAS Key Lab Mental Hlth, Inst Psychol, Beijing 100101, Peoples R China 8.Capital Med Univ, Beijing Key Lab Mental Disorders, Dept Psychiat, Beijing Anding Hosp, Beijing 100088, Peoples R China 9.Capital Med Univ, Ctr Schizophrenia, Beijing Inst Brain Disorders, Minist Sci & Technol, Beijing 100088, Peoples R China 10.Capital Med Univ, Lab Brain Disorders, Minist Sci & Technol, Beijing 100088, Peoples R China 11.NIMH, Unit Stat Genom, Intramural Res Programs, NIH, Bethesda, MD 20892 USA 12.Univ Illinois, Inst Human Genet, Chicago, IL 60607 USA 13.China Med Univ, Affiliated Hosp 1, Dept Psychiat, Shenyang 110122, Peoples R China 14.Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Shanghai 200031, Peoples R China 15.Zhengzhou Univ, Affiliated Hosp 1, Dept Psychiat, Zhengzhou 450052, Peoples R China
Recommended Citation:
Tang, Jinsong,Fan, Yu,Li, Hong,et al. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia[J]. JOURNAL OF GENETICS AND GENOMICS,2017,44(6):295-306.
