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

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

doi:10.1016/j.jgg.2017.05.005

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

J Genet Genomics. 2017 Jun 20;44(6):295-306. doi: 10.1016/j.jgg.2017.05.005. Epub 2017 Jun 8.

Authors

Jinsong Tang¹, Yu Fan², Hong Li³, Qun Xiang⁴, Deng-Feng Zhang², Zongchang Li¹, Ying He¹, Yanhui Liao¹, Ya Wang⁵, Fan He⁶, Fengyu Zhang¹, Yin Yao Shugart⁷, Chunyu Liu⁸, Yanqing Tang⁹, Raymond C K Chan¹⁰, Chuan-Yue Wang¹¹, Yong-Gang Yao¹², Xiaogang Chen¹³

Affiliations

¹ Institute of Mental Health, National Clinical Research Center for Mental Health Disorders and National Technology Institute of Psychiatry, and Key Laboratory of Psychiatry and Mental Health of Hunan Province, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
³ Institute of Mental Health, National Clinical Research Center for Mental Health Disorders and National Technology Institute of Psychiatry, and Key Laboratory of Psychiatry and Mental Health of Hunan Province, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁴ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China.
⁵ Neuropsychology and Applied Cognitive Neuroscience Laboratory, and CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, and Center of Schizophrenia, Beijing Institute for Brain Disorders and Laboratory of Brain Disorders of the Ministry of Science and Technology, Capital Medical University, Beijing 100088, China.
⁷ Unit on Statistical Genomics, Intramural Research Programs, National Institute of Mental Health, NIH, Bethesda 20892, USA.
⁸ Institute of Human Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
⁹ Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110122, China. Electronic address: yanqingtang@163.com.
¹⁰ Neuropsychology and Applied Cognitive Neuroscience Laboratory, and CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: rckchan@psych.ac.cn.
¹¹ Beijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, and Center of Schizophrenia, Beijing Institute for Brain Disorders and Laboratory of Brain Disorders of the Ministry of Science and Technology, Capital Medical University, Beijing 100088, China. Electronic address: wang.cy@163.net.
¹² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: yaoyg@mail.kiz.ac.cn.
¹³ Institute of Mental Health, National Clinical Research Center for Mental Health Disorders and National Technology Institute of Psychiatry, and Key Laboratory of Psychiatry and Mental Health of Hunan Province, The Second Xiangya Hospital, Central South University, Changsha 410011, China. Electronic address: chenxghn@163.com.

PMID: 28645778
DOI: 10.1016/j.jgg.2017.05.005

Abstract

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.

Keywords: Combined effect; De novo mutation; Monozygotic twin; Schizophrenia; Susceptibility; Whole-genome sequencing.

MeSH terms

Adult
DNA Copy Number Variations
Female
Genetic Predisposition to Disease / genetics*
Humans
Male
Pedigree
Polymorphism, Single Nucleotide
Reelin Protein
Schizophrenia / genetics*
Twins, Monozygotic / genetics*
Whole Genome Sequencing*