期刊
JOURNAL OF GENETICS AND GENOMICS
卷 44, 期 6, 页码 295-306出版社
SCIENCE PRESS
DOI: 10.1016/j.jgg.2017.05.005
关键词
Whole-genome sequencing; Schizophrenia; Monozygotic twin; De novo mutation; Combined effect; Susceptibility
资金
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB02020003, XDB02030002]
- Bureau of Frontier Sciences and Education, Chinese Academy of Sciences [QYZDJ-SSW-SMC005]
- National Natural Science Foundation of China [81088001, 81271484, 81471361, 81371480]
- 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]
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.
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