Dylan J. Kiltschewskij, William R. Reay, Murray J. Cairns
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Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (<i>n</i> = 644) from additional cohorts and a non-psychiatric comparison group (<i>n</i> = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Schizophrenia is associated with altered DNA methylation variance\",\"authors\":\"Dylan J. Kiltschewskij, William R. Reay, Murray J. Cairns\",\"doi\":\"10.1038/s41380-024-02749-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. 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引用次数: 0
摘要
遗传和环境风险因素的不同组合被认为是精神分裂症等精神疾病个体间表型异质性的基础。虽然精神分裂症的全表观基因组关联研究发现了平均 DNA 甲基化水平的广泛改变,但对 DNA 甲基化差异的位置和影响却知之甚少,而这可能会导致表型和治疗反应的异质性。为了探讨这个问题,我们利用由 1036 名精神分裂症患者和 954 名非精神疾病对照者组成的三个队列,对精神分裂症患者的血液 DNA 甲基化差异进行了迄今为止最大规模的荟萃分析。令人惊讶的是,在与精神分裂症相关的 213 个可变甲基化位点(VMPs)中,只有一小部分(0.1%)(Benjamini-Hochberg FDR <0.05)与差异甲基化位点(DMPs;病例与对照组之间存在平均变化的位点)共享。研究发现,这些来自血液的 VMPs 在以前与精神分裂症相关的基因中以及在脑丰富基因中的比例过高,有证据表明小脑、海马、前额叶皮层或纹状体中的 VMPs 发生了一致的变化。我们还观察到表观遗传协方差与具有临床意义的指标有关,包括发病年龄、认知缺陷和症状严重程度。我们还在其他队列的首发精神病患者(n = 644)和非精神病对比组(n = 633)中发现了显著的 VMP。总之,这些发现表明精神分裂症与 DNA 甲基化变异的显著变化有关,这可能会导致个体间的异质性。
Schizophrenia is associated with altered DNA methylation variance
Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR < 0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n = 644) from additional cohorts and a non-psychiatric comparison group (n = 633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.