Human placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal DNAme in the uncomplicated term placenta (n = 343) using the Illumina 450K array. At a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex and replicated in an independent cohort of samples (n = 293). Several of these differentially methylated CpG sites were part of larger correlated regions of sex differential DNAme. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Patterns of autosomal DNAme at these 162 CpGs were significantly associated with maternal age (in males) and newborn birthweight standard deviation (in females). Our results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.

中文翻译：

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足月胎盘常染色体 DNA 甲基化性别差异的跨队列分析

人类胎盘 DNA 甲基化 (DNAme) 数据是研究妊娠期间性别差异的宝贵资源，因为分娩后的 DNAme 图谱反映了妊娠期间基因表达模式和暴露的累积效应。在这里，我们使用 Illumina 450K 阵列对简单的足月胎盘 (n = 343) 中常染色体 DNAme 的性别差异进行了分析。在错误发现率 < 0.05 且 DNAme beta 值的平均性别差异 > 0.10 的情况下，我们鉴定了 162 个常染色体 CpG 位点，这些位点按性别差异甲基化，并在独立样本队列中复制 (n = 293)。这些差异甲基化的 CpG 位点中有几个是性别差异 DNAme 较大相关区域的一部分。尽管总体 DNAme 水平不因性别而存在差异，但大多数显着差异甲基化的 CpG 在男性胎盘中甲基化程度更高，这与体细胞组织差异甲基化分析中看到的情况相反。这 162 个 CpG 的常染色体 DNAme 模式与母亲年龄（男性）和新生儿出生体重标准差（女性）显着相关。我们的结果对人类胎盘中常染色体 DNAme 的性别差异进行了全面分析。我们报告了一系列高可信度的常染色体性别相关差异甲基化 CpG，并确定了这些位点的几个关键特征，这些特征表明它们与正常妊娠和复杂妊娠中观察到的性别差异相关。