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A higher dysregulation burden of brain DNA methylation in female patients implicated in the sex bias of Schizophrenia

Molecular Psychiatry volumeĀ 28,Ā pages 4842ā€“4852 (2023)Cite this article

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Abstract

Sex differences are pervasive in schizophrenia (SCZ), but the extent and magnitude of DNA methylation (DNAm) changes underlying these differences remain uncharacterized. In this study, sex-stratified differential DNAm analysis was performed in postmortem brain samples from 117 SCZ and 137 controls, partitioned into discovery and replication datasets. Three differentially methylated positions (DMPs) were identified (adj.pā€‰<ā€‰0.05) in females and 29 DMPs in males without overlap between them. Over 81% of these sex-stratified DMPs were directionally consistent between sexes but with different effect sizes. Females experienced larger magnitude of DNAm changes and more DMPs (based on data of equal sample size) than males, contributing to a higher dysregulation burden of DNAm in females SCZ. Additionally, despite similar proportions of female-related DMPs (fDMPs, 8%) being under genetic control compared with males (10%), significant enrichment of DMP-related single nucleotide polymorphisms (SNPs) in signals of genome-wide association studies was identified only in fDMPs. One DMP in each sex connected the SNPs and gene expression of CALHM1 in females and CCDC149 in males. PPI subnetworks revealed that both female- and male-related differential DNAm interacted with synapse-related dysregulation. Immune-related pathways were unique for females and neuron-related pathways were associated with males. This study reveals remarkable quantitative differences in DNAm-related sexual dimorphism in SCZ and that females have a higher dysregulation burden of SCZ-associated DNAm than males.

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Fig. 1: Sex-stratified differential DNAm in SCZ.
Fig. 2: Comparing the magnitude of DNAm changes between females and males with SCZ.
Fig. 3: Sex-stratified DMPs mediate genetic effects on gene expression.
Fig. 4: Sex-specific PPI subnetworks and biological processes.
Fig. 5: The theoretical model for sex-biased DNAm burden hypothesis of SCZ.

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Data availability

All data are available in the main text or the supplementary materials. Published DNAm datasets analyzed in this study are available on Gene Expression Omnibus (accession No. GSE74193, GSE61431 and GSE61380).

Code availability

The code of this work can be found at https://github.com/zhoujiaqi704/Sex-stratified-differential-DNAm-in-schizophrenia.

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Acknowledgements

We thank Richard F. Kopp from SUNY Upstate Medical University, for his critical reading and language editing, which greatly improved the manuscript. We gratefully acknowledge the families of the brain donors, without whom this work would not have been possible. This work was supported in part by the High Performance Computing Center of Central South University.

Funding

FundingThis work was supported by the National Natural Science Foundation of China (Grants Nos. 82022024, 31970572, 31871276), the National Key R&D Project of China (Grants No. 2016YFC1306000), the science and technology innovation Program of Hunan Province, Innovation-driven Project of Central South University (Grant Nos. 2020CX003) (to C. Chen), and NIH grants U01MH122591, 1U01MH116489, 1R01MH110920 (to C. Liu).

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Authors and Affiliations

  1. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and the Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China

    Jiaqi Zhou,Ā Miao Li,Ā Yu Chen,Ā Jiacheng Dai,Ā Chunyu LiuĀ &Ā Chao Chen

  2. State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, 200438, China

    Jiaqi ZhouĀ &Ā Jiacheng Dai

  3. Department of Medicine, Harvard Medical School, Boston, MA, 02114, USA

    Yan Xia

  4. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02114, USA

    Yan XiaĀ &Ā Yu Chen

  5. Analytic and Translational Genetics unit, Massachusetts General Hospital, Boston, MA, 02114, USA

    Yan Xia

  6. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, 13210, USA

    Chunyu Liu

  7. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan, 410078, China

    Chao Chen

  8. National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China

    Chao Chen

  9. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China

    Chao Chen

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Contributions

CL, CC and YX designed and guided the study. JZ and ML collected and download the datasets. JZ, ML and YC preprocessed the data. JZ, ML, YC and JD did the bioinformatics analyses. JZ wrote the manuscript with substantive edits from CL, CC, YX and YC.

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Correspondence to Yan Xia, Chunyu Liu or Chao Chen.

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Zhou, J., Xia, Y., Li, M. et al. A higher dysregulation burden of brain DNA methylation in female patients implicated in the sex bias of Schizophrenia. Mol Psychiatry 28, 4842ā€“4852 (2023). https://doi.org/10.1038/s41380-023-02243-4

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