Although male-female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas from full term pregnancies (N = 532 samples), 5,212 CpGs met genome-wide significance (p < 1E-8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E-14), chemokine activity (FDR p-value = 1.56E-2), and eosinophil migration (FDR p-value = 1.83E-2). Nine differentially methylated regions were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life.

中文翻译：

---

大规模胎盘DNA甲基化的大规模分析揭示了胎儿性别特异性差异甲基化CpG位点和区域

尽管已经观察到胎盘结构和功能的男女差异，但对其分子基础的了解却很少。在这里，我们提出了14个可公开获得的胎盘DNA甲基化（DNAm）微阵列数据集的大型分析，以识别单个CpGs和与胎儿性别相关的区域。在足月妊娠胎盘的发现数据集中（N = 532个样本），有5,212个CpGs达到了全基因组范围的意义（p <1E-8），并且富含诸如角质化等途径（FDR p值= 7.37E-14）。 ，趋化因子活性（FDR p值= 1.56E-2）和嗜酸性粒细胞迁移（FDR p值= 1.83E-2）。鉴定出9个差异甲基化区域（fwerArea <0。1）在ZNF300启动子中包含一个区域，该区域从怀孕的早期时间点开始在样品中显示出一致的DNAm差异，并且似乎主要受滋养层细胞类型的影响所驱动。我们描述了迄今为止最大的胎盘DNAm中胎儿性别差异的研究，揭示了表征性别的胎盘功能和生命后期健康结局的基因和途径。