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.

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之间表型异质性的基础。虽然精神分裂症的表观基因组关联研究已经发现平均 DNA 甲基化水平的广泛改变，但人们对 DNA 甲基化变异的位置和影响知之甚少，而 DNA 甲基化变异可能导致表型和治疗反应异质性。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 甲基化变异进行了迄今为止最大规模的荟萃分析。令人惊讶的是，与精神分裂症相关的 213 个可变甲基化位置 (VMP) (Benjamini-Hochberg FDR < 0.05) 中只有一小部分 (0.1%) 与差异甲基化位置 (DMP；病例和对照之间平均变化的位点) 相同。这些血液来源的 VMP 在先前与精神分裂症相关的基因和大脑富集基因中被发现过多，有证据表明小脑、海马、前额皮质或纹状体中的 VMP 发生了一致的变化。还观察到临床显着指标的表观遗传协方差，包括发病年龄、认知缺陷和症状严重程度。我们还在其他队列和非精神病对照组 ( n = 633) 的首发精神病个体 ( n = 644) 中发现了显着的 VMP。总的来说，这些发现表明精神分裂症与 DNA 甲基化变异的显着变化有关，这可能导致个体间的异质性。