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Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype

Maolin Hu, View ORCID ProfileYan Xia, Xiaofen Zong, John A. Sweeney, Jeffrey R Bishop, Yanhui Liao, Gina Giase, Bingshan Li, Leah H. Rubin, Yunpeng Wang, Zongchang Li, Ying He, Xiaogang Chen, View ORCID ProfileChunyu Liu, View ORCID ProfileChao Chen, Jinsong Tang
doi: https://doi.org/10.1101/2020.03.31.018283
Maolin Hu
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Yan Xia
2Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
3Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY
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  • ORCID record for Yan Xia
Xiaofen Zong
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
4Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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John A. Sweeney
5Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio
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Jeffrey R Bishop
6Department of Experimental and Clinical Pharmacology and Department of Psychiatry, University of Minnesota, Minneapolis, MN
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Yanhui Liao
7Department of Psychiatry, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
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Gina Giase
8Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
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Bingshan Li
9Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN
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Leah H. Rubin
10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
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Yunpeng Wang
11Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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Zongchang Li
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
2Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
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Ying He
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Xiaogang Chen
1Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
13Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
14National Clinical Research Center on Mental Disorders, Changsha, Hunan 410011, China
15National Technology Institute on Mental Disorders, Changsha, Hunan 410011, China
16Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan 410011, China
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  • For correspondence: tangjinsong@zju.edu.cn liucy@uic.edu chenchao@sklmg.edu.cn chenxiaogang@csu.edu.cn
Chunyu Liu
2Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
3Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY
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  • For correspondence: tangjinsong@zju.edu.cn liucy@uic.edu chenchao@sklmg.edu.cn chenxiaogang@csu.edu.cn
Chao Chen
2Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
12National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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  • For correspondence: tangjinsong@zju.edu.cn liucy@uic.edu chenchao@sklmg.edu.cn chenxiaogang@csu.edu.cn
Jinsong Tang
7Department of Psychiatry, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
12National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
13Mental Health Institute, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
14National Clinical Research Center on Mental Disorders, Changsha, Hunan 410011, China
15National Technology Institute on Mental Disorders, Changsha, Hunan 410011, China
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  • For correspondence: tangjinsong@zju.edu.cn liucy@uic.edu chenchao@sklmg.edu.cn chenxiaogang@csu.edu.cn
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ABSTRACT

Today, second generation anti-psychotics such as clozapine and risperidone are the favored treatment for schizophrenia. Yet, the absence of relevant biomarkers that can decode their neurobiological effect shackles our ability to accurately predict and track response to treatment. While researchers have investigated DNA methylation as a biomarker for schizophrenia risk, none have performed a systematic analysis of the effect of antipsychotics upon DNA methylation. We hypothesize that disease-related methylation changes occur before treatment, and that acute antipsychotic treatment may affect DNA methylation. We designed a longitudinal DNA methylation study to estimate risperidone’s effect on DNA methylation and how changes in DNA methylation might influence risperidone’s therapeutic effect on behavioral and neuroimaging phenotypes. Thirty-eight patients with first-episode drug-naïve schizophrenia (FES) and 38 demographically-matched individuals (healthy controls) participated. We identified brain related pathways enriched in 8,204 FES-associated methylation sites. Risperidone administration altered methylation in 6,143 CpG DNA sites. Post-treatment FES associated with methylation in 6760 CpG sites. Majority of the DNA methylation changes were treatment effect in the overall CpG sites, the FES associated CpG sites, and risperidone associated CpG sites, except for the post-treatment FES associated CpG sites. There were 590 DNA methylation cites normalized by risperidone treatment. The methylation changes of these 590 CpG sites were related to alterations in symptom severity, spontaneous neurophysiological activity, and cognitive function. To our knowledge, this is the first longitudinal methylation study of drug treatment effect and side effect in psychiatric disorders to include parallel studies of neuroimaging and cognitive phenotypes. We identified FES-associated CpG sites not confounded by drug treatment as potential SCZ biomarkers. The normalization effect of risperidone monotherapy suggests that DNA methylation changes may serve as a predictive biomarker for treatment effect. The constructed methylation-phenotype network revealed a relationship between methylation and a wide range of biological and psychological variables.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding and Disclosure This work was supported by grants from the National Natural Science Foundation of China (81871057 and 81371480 to J.T;81271484 and 81471361 to X.C.; 31970572, 81401114 and 31571312 to C.C.) the National Key Plan for Scientific Research and Development of China (2016YFC1306000) (to C. C.) and NIH grant 1 U01 MH103340-01, 1R01ES024988 (to C. L.), MH083888 (to J.R.B.). Wuhan Science and Technology Bureau grant (2017060201010169 to M. H.). Central South University Graduate Project grant (502221702 to Y.X.).

    The authors have nothing to disclose.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 09, 2020.
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Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype
Maolin Hu, Yan Xia, Xiaofen Zong, John A. Sweeney, Jeffrey R Bishop, Yanhui Liao, Gina Giase, Bingshan Li, Leah H. Rubin, Yunpeng Wang, Zongchang Li, Ying He, Xiaogang Chen, Chunyu Liu, Chao Chen, Jinsong Tang
bioRxiv 2020.03.31.018283; doi: https://doi.org/10.1101/2020.03.31.018283
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Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype
Maolin Hu, Yan Xia, Xiaofen Zong, John A. Sweeney, Jeffrey R Bishop, Yanhui Liao, Gina Giase, Bingshan Li, Leah H. Rubin, Yunpeng Wang, Zongchang Li, Ying He, Xiaogang Chen, Chunyu Liu, Chao Chen, Jinsong Tang
bioRxiv 2020.03.31.018283; doi: https://doi.org/10.1101/2020.03.31.018283

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