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DNA 甲基化荟萃分析揭示了精神分裂症中的细胞变化和治疗抵抗性精神分裂症的标志物。

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

机构信息

University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom.

Division of Psychiatry, University College London, London, United Kingdom.

出版信息

Elife. 2021 Feb 26;10:e58430. doi: 10.7554/eLife.58430.

DOI:10.7554/eLife.58430
PMID:33646943
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8009672/
Abstract

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

摘要

我们对来自七个独立队列的 4483 名参与者的血液 DNA 甲基化图谱进行了系统分析，确定了与精神病、精神分裂症和治疗抵抗性精神分裂症相关的差异甲基化位置（DMP）。精神病病例的血液细胞比例和吸烟暴露的衡量指标存在显著差异，这些差异在治疗抵抗性精神分裂症患者中最为明显。我们实施了严格的元分析管道，对数据集进行了全基因组关联研究（EWAS）结果的荟萃分析，确定了 95 个与精神病相关的 DMP 和 1048 个与精神分裂症相关的 DMP，有证据表明这些 DMP 与疾病遗传关联研究提名的区域存在共定位。许多与精神分裂症相关的 DNA 甲基化差异仅存在于治疗抵抗性精神分裂症患者中，这可能反映了对非典型抗精神病药氯氮平的暴露。我们的研究结果强调了如何利用 DNA 甲基化数据来识别与精神病相关的生理（例如，细胞计数差异）和环境（例如，吸烟）因素，以及治疗抵抗性精神分裂症的分子生物标志物。

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