Abstract
Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of \({\mathrm{1}}{\mathrm{.34}} \times {\mathrm{10}}^{{\mathrm{ - 12}}}\), \({\mathrm{1}}{\mathrm{.15}} \times {\mathrm{10}}^{{\mathrm{ - 11}}}\), and \({\mathrm{3}}{\mathrm{.11}} \times {\mathrm{10}}^{{\mathrm{ - 11}}}\), respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.
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Data availability
Code used in the analyses is available to download from https://github.com/Mingrui-Li1992/SZ_methylation. All data can be viewed in NODE (http://www.biosino.org/node) by pasting the accession OEP001178 into the text search box or through the URL: http://www.biosino.org/node/project/detail/ OEP001178.
Change history
04 January 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41380-020-01013-w
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Acknowledgements
We are grateful to the patients, healthy volunteers, and their families who contributed to this study. This study was funded by School of Life Sciences of Fudan University, as a start-up capital for Dr. Yin Yao, and was partially funded by Beijing HuiLongGuan Hospital. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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ML performed the DNA methylation analysis, result interpretation and discussion, and wrote the manuscript; YL contributed to sample recruitment and preparation; HQ participated in the data analysis pipeline construction, result discussion and interpretation; JDT helped revise the manuscript and provided insightful thoughts to the data interpretation; ML performed the co-localization analysis; CQ contributed to literature review and experimental procedure supervision; JL and QL contributed to literature review; FF, MG, JH, JT, and FY participated in the sample recruitment; YY and YT conceived the study, co-supervised study manuscript writing, interpreted the results and finalized the manuscript. All authors approved the final manuscript.
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Li, M., Li, Y., Qin, H. et al. Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population. Mol Psychiatry 26, 4475–4485 (2021). https://doi.org/10.1038/s41380-020-00968-0
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DOI: https://doi.org/10.1038/s41380-020-00968-0
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