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Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function

Molecular Psychiatry volume 26, pages 6630–6642 (2021)Cite this article

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Abstract

The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.

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Fig. 1: Schematic describing the method of detecting ASM in MZ twin pairs.
Fig. 2: Characteristics of psyASM genes.
Fig. 3: ASM switching-mediated EIPR1 downregulation in schizophrenia.
Fig. 4: Competitive binding of the repressive TFs at a psyASM switching regulatory locus induced dysregulated EIPR1 expression.
Fig. 5: EIPR1 gain of function promotes neural development and vesicle trafficking.

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Acknowledgements

We thank the National Natural Science Foundation of China [grant number 81671333, 82001411], the Guangdong Science and Technology Foundation [grant number 2019B030316032, 2017A050506026], China Postdoctoral Science Foundation [grant number 2020M682806], and the Science and Technology Program of Guangzhou [grant number 201804010259] for providing financial supports.

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  1. These authors contributed equally: Qiyang Li, Zhongju Wang, Lu Zong, Linyan Ye

Authors and Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China

    Qiyang Li, Zhongju Wang, Lu Zong, Linyan Ye, Junping Ye, Haiyan Ou, Bo Guo, Wenquan Liang, Jian Zhang, Yong Long, Yu Hou, Lin Zhou, Shufen Li & Cunyou Zhao

  2. Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China

    Qiyang Li, Zhongju Wang, Linyan Ye, Junping Ye, Bo Guo, Wenquan Liang, Shufen Li & Cunyou Zhao

  3. Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Lu Zong

  4. The Third People’s Hospital of Zhongshan, Zhongshan, Guangdong, China

    Tingyun Jiang

  5. Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China

    Qiong Yang, Fengchun Wu & Xingbing Huang

  6. Guangdong General Hospital, Guangdong Academy of Medical Science and Guangdong Mental Health Center, Guangzhou, China

    Xianzhen Zheng

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Contributions

Conceived and designed the experiments: QL, ZW, LZ, and CZ. Performed the experiments: QL, LZ, LY, BG, WL, YL, YH, LZ, and SL. Analyzed the data: QY, ZW, LZ, JY, HO, and CZ. Collected and diagnosed the control and patient subjects: TJ, QY, XZ, FW, and XH. Wrote the paper: QL, ZW, LZ, and CZ.

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Correspondence to Cunyou Zhao.

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Li, Q., Wang, Z., Zong, L. et al. Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function. Mol Psychiatry 26, 6630–6642 (2021). https://doi.org/10.1038/s41380-021-01126-w

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