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Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Schizophrenia | Research article

Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene

Authors: Chengcheng Zhang, Xiaojing Li, Liansheng Zhao, Rong Liang, Wei Deng, Wanjun Guo, Qiang Wang, Xun Hu, Xiangdong Du, Pak Chung Sham, Xiongjian Luo, Tao Li

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Identifying the causal genes at the risk loci and elucidating their roles in schizophrenia (SCZ) pathogenesis remain significant challenges. To explore risk variants associated with gene expression in the human brain and to identify genes whose expression change may contribute to the susceptibility of SCZ, here we report a comprehensive integrative study on SCZ.

Methods

We systematically integrated the genetic associations from a large-scale SCZ GWAS (N = 56,418) and brain expression quantitative trait loci (eQTL) data (N = 175) using a Bayesian statistical framework (Sherlock) and Summary data-based Mendelian Randomization (SMR). We also measured brain structure of 86 first-episode antipsychotic-naive schizophrenia patients and 152 healthy controls with the structural MRI.

Results

Both Sherlock (P = 3. 38 × 10−6) and SMR (P = 1. 90 × 10−8) analyses showed that TYW5 mRNA expression was significantly associated with risk of SCZ. Brain-based studies also identified a significant association between TYW5 protein abundance and SCZ. The single-nucleotide polymorphism rs203772 showed significant association with SCZ and the risk allele is associated with higher transcriptional level of TYW5 in the prefrontal cortex. We further found that TYW5 was significantly upregulated in the brain tissues of SCZ cases compared with controls. In addition, TYW5 expression was also significantly higher in neurons induced from pluripotent stem cells of schizophrenia cases compared with controls. Finally, combining analysis of genotyping and MRI data showed that rs203772 was significantly associated with gray matter volume of the right middle frontal gyrus and left precuneus.

Conclusions

We confirmed that TYW5 is a risk gene for SCZ. Our results provide useful information toward a better understanding of the genetic mechanism of TYW5 in risk of SCZ.
Appendix
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Metadata
Title
Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene
Authors
Chengcheng Zhang
Xiaojing Li
Liansheng Zhao
Rong Liang
Wei Deng
Wanjun Guo
Qiang Wang
Xun Hu
Xiangdong Du
Pak Chung Sham
Xiongjian Luo
Tao Li
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Schizophrenia
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02363-8

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