Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.

精神分裂症流行病学和临床特征的性别差异是众所周知的；然而，这些差异背后的分子机制仍不清楚。此外，精神分裂症表观基因组范围关联研究（EWAS）的性别分层荟萃分析的潜在优势尚未得到研究。在这里，我们进行了性别分层 EWAS 荟萃分析，以调查性别分层是否可以改善发现，并识别精神分裂症中的差异甲基化区域 (DMR)。来自三个公开数据集的 1519 例精神分裂症患者（男性n  = 989，女性n  = 530）和 1723 名对照者（男性n  = 997，女性n  = 726）的外周血 DNA 甲基化数据，以及 TOP 队列是元数据分析比较特定性别、性别分层和性别调整的 EWAS。通过多甲基化评分（PMS）评估每个模型的预测能力。性别分层模型中鉴定出的与精神分裂症相关的差异甲基化位置的数量高于性别调整模型。我们在性别分层分析中确定了 20 种与精神分裂症相关的 DMR。在预测精神分裂症方面，性别分层分析的经前综合症优于性别调整分析。值得注意的是，来自性别分层和仅限女性分析的经前综合症，但不是来自性别调整或仅限男性分析的经前综合症，显着预测了男性的精神分裂症。研究结果表明，按性别分层的 EWAS 荟萃分析可以提高对精神分裂症相关表观遗传变化的识别，并强调性别与精神分裂症状态在 DNA 甲基化方面的相互作用。性别特异性 DNA 甲基化可能对精准精神病学和精神分裂症分层治疗的发展具有潜在影响。