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Brain transcriptome-wide association study implicates novel risk genes underlying schizophrenia risk

Published online by Cambridge University Press:  24 April 2023

Chengcheng Zhang ,
Xiaojing Li ,
Liansheng Zhao ,
Wanjun Guo ,
Wei Deng ,
Qiang Wang ,
Xun Hu ,
Xiangdong Du ,
Pak Chung Sham  and
Xiongjian Luo
...Show all authors
Chengcheng Zhang
Affiliation:
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Xiaojing Li
Affiliation:
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Liansheng Zhao
Affiliation:
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Wanjun Guo
Affiliation:
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Wei Deng
Affiliation:
Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Qiang Wang
Affiliation:
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Xun Hu
Affiliation:
The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Xiangdong Du
Affiliation:
Suzhou Psychiatric Hospital, Soochow University's Affiliated Guangji Hospital, Suzhou, Jiangsu, China
Pak Chung Sham
Affiliation:
Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China Centre for PanorOmic Sciences, The University of Hong Kong, Hong Kong SAR, China State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China
Xiongjian Luo
Affiliation:
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China
Tao Li*
Affiliation:
Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China
*
Corresponding author: Tao Li, E-mail: litaozjusc@zju.edu.cn
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Abstract

Background

To identify risk genes whose expression are regulated by the reported risk variants and to explore the potential regulatory mechanism in schizophrenia (SCZ).

Methods

We systematically integrated three independent brain expression quantitative traits (eQTLs) (CommonMind, GTEx, and BrainSeq Phase 2, a total of 1039 individuals) and GWAS data (56 418 cases and 78 818 controls), with the use of transcriptome-wide association study (TWAS). Diffusion magnetic resonance imaging was utilized to quantify the integrity of white matter bundles and determine whether polygenic risk of novel genes linked to brain structure was present in patients with first-episode antipsychotic SCZ.

Results

TWAS showed that eight risk genes (CORO7, DDAH2, DDHD2, ELAC2, GLT8D1, PCDHA8, THOC7, and TYW5) reached transcriptome-wide significance (TWS) level. These findings were confirmed by an independent integrative approach (i.e. Sherlock). We further conducted conditional analyses and identified the potential risk genes that driven the TWAS association signal in each locus. Gene expression analysis showed that several TWS genes (including CORO7, DDAH2, DDHD2, ELAC2, GLT8D1, THOC7 and TYW5) were dysregulated in the dorsolateral prefrontal cortex of SCZ cases compared with controls. TWS genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and microglia. Finally, SCZ cases had a substantially greater TWS genes-based polygenic risk (PRS) compared to controls, and we showed that fractional anisotropy of the cingulum-hippocampus mediates the influence of TWS genes PRS on SCZ.

Conclusions

Our findings identified novel SCZ risk genes and highlighted the importance of the TWS genes in frontal-limbic dysfunctions in SCZ, indicating possible therapeutic targets.

Keywords

eQTLGWASschizophreniaTWASwhite matter tract
Type
Original Article
Information
Psychological Medicine , Volume 53 , Issue 14 , October 2023 , pp. 6867 - 6877
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Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press

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