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Multi-omics analysis identifies rare variation in leptin/PPAR gene sets and hypermethylation of ABCG1 contribute to antipsychotics-induced metabolic syndromes

Molecular Psychiatry volume 27, pages 5195–5205 (2022)Cite this article

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Abstract

Antipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations. By population-based omics analysis, we revealed that rare functional variants across in the leptin and peroxisome proliferator-activated receptors (PPARs) gene sets were imbalanced with rare functional variants across the APs-induced Mets and Non-Mets cohort. Besides, we discovered that APs-induced Mets are hypermethylated in ABCG1 (chr21:43642166–43642366, adjusted P < 0.05) than Non-Mets, and hypermethylation of this area was associated with higher TC (total cholesterol) and TG (triglycerides) levels in HepG2 cells. Candidate genes from omics studies were furtherly screened in C. elegans and 17 gene have been verified to associated with olanzapine (OLA) induced fat deposit. Among them, several genes were expressed differentially in Mets cohort and APs-induced in vitro/in vivo models compared to controls, demonstrating the validity of omics study. Overexpression one of the most significant gene, PTPN11, exhibited compromised glucose responses and insulin resistance. Pharmacologic inhibition of PTPN11 protected HepG2 cell from APs-induced insulin resistance. These findings provide important insights into our understanding of the mechanism of the APs-induced Mets.

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Fig. 1: Details of the genome-wide top hit rs12930712.
Fig. 2: Epigenome-wide association results and enrichment analysis of top-100 CpG sites regarding Mets in schizophrenia cohorts.
Fig. 3: Differentially methylated regions (DMRs) associated with Mets in the schizophrenia cohort.
Fig. 4: RNAi screen identifies genes associated with OLA-induced fat deposit in C. elegans.
Fig. 5: Gene expression level in models of APs-induced Mets and pharmacological inhibition of PTPN11 rescues OLA-induced Mets in vitro.

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Data availability

Raw data have been deposited in the China National Center for Bioinformation and are available upon request to SQ (chinsir@sjtu.edu.cn). All other data are available in the Supplementary Information.

Code availability

Scripts used to generate the results are available on request from the corresponding author.

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Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (81773818, 81273596, 30900799, 81671326, 81503051), National key research and development program (2016YFC0905000, 2016YFC0905002, 2016YFC1200200, 2016YFC0906400), Shanghai science and Technology Innovation Fund (20DZ2202000, 21002411100), Major projects of scientific and technological innovation 2030 (2021ZD0200801), Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), The 4th Three-year Action Plan for Public Health of Shanghai (The Project No.: 15GWZK0101), 111 project, Shanghai Pujiang Program (17PJD020), Natural Science Foundation of Shanghai (22ZR1430300), Shanghai Key Laboratory of Psychotic Disorders (13dz2260500), Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) Program of Shanghai Jiao Tong University (2020GDND04, 2021GDND02), China Postdoctoral Science Foundation (2017M621488), Youth Backbone Teacher Training Project of Jiangsu University (Jing Sun, 2015), Effective & Toxicity Monitoring Innovative Practice Center for Jiangsu University Food Pharmaceutical Specialty (2020).

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Author notes

  1. These authors contributed equally: Wei Zhou, Jing Sun, Cong Huai.

Authors and Affiliations

  1. Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China

    Wei Zhou, Cong Huai, Luan Chen, Hao Wu, Yidan Sun, Mo Li, Jinhang Zhu, Yingtian Zhang, Muyun Wei, Yujian Guo, Sijia Huang, Na Zhang, Ruoxi Shen, Ying Zhang, Huihui Du, Lin He, Lu Shen & Shengying Qin

  2. Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang, China

    Jing Sun & Yunxi Liu

  3. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Zhenghui Yi & Qinyu Lv

  4. The Fourth People’s Hospital of Wuhu, Wuhu, China

    Chuanfu Song & Wenli Zhu

  5. Jining Medical University, Department of Psychiatry, School of Mental Health, Psychiatry Genetic Lab PSYG Lab, Jining, China

    Chuanxin Liu

  6. Fuzhou Neuro-Psychiatric Hospital affiliated to Fujian Medical University, Fuzhou, China

    Saizheng Weng

  7. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Runshuai Zhang & Lianfeng Wu

  8. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China

    Runshuai Zhang & Lianfeng Wu

  9. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China

    Runshuai Zhang & Lianfeng Wu

  10. Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Hailiang Huang

  11. Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Xiaofang Sun

  12. Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, Guangdong, China

    Xiaofang Sun

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  1. Wei Zhou
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Contributions

ZW performed the data analysis, experiments and wrote the paper; SJ, LYX, and HC contributed to in vitro and in vivo experiments. YZH, LQY, SCF, ZWL, LCX, WSZ, HS, WH, ZN, ZY, and HS contributed to sample recruitment and preparation; ZW, GYJ, WH, HSJ, ZN, and ZY contributed to sample and library prepare; ZW, HC, SYD, LM, DHH, SRX, and ZJH contributed to data analysis; ZW, WH, ZRS, WLF, and ZYT contributed to C. elegans experiments; HC, LM, CL, HHL, WMY, SXF, and HL revised the paper; QSY designed and supervised the whole study.

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Correspondence to Shengying Qin.

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Zhou, W., Sun, J., Huai, C. et al. Multi-omics analysis identifies rare variation in leptin/PPAR gene sets and hypermethylation of ABCG1 contribute to antipsychotics-induced metabolic syndromes. Mol Psychiatry 27, 5195–5205 (2022). https://doi.org/10.1038/s41380-022-01759-5

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