Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.
Genome Center, University of California, Davis, CA, USA.
Hum Mol Genet. 2019 Aug 15;28(16):2659-2674. doi: 10.1093/hmg/ddz084.
DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies. A total of 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typically developing controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing and correlated with expression differences in brain. Methylation at CYP2E1 associated with both ASD diagnosis and genotype within the DMR. In contrast, methylation at IRS2 was unaffected by within DMR genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.
DNA 甲基化作用于与自闭症谱系障碍（ASD）相关的遗传和环境因素的界面。胎盘通常在出生时被丢弃，但它是一种潜在的富含可预测儿童 ASD 的 DNA 甲基化模式的丰富来源。在这里，我们对前瞻性 MARBLES（婴儿自闭症风险标志物-学习早期迹象）研究中高危妊娠的胎盘进行了全甲基化组分析。共有 400 个差异甲基化区域（DMR）区分了从以后被诊断为 ASD 的儿童中储存的胎盘与正常发育对照。与神经元发育功能相关的 596 个基因的启动子明显富集了这些 ASD DMR，并且与遗传 ASD 风险重叠。CYP2E1 和 IRS2 的 ASD DMR 达到了全基因组显著水平，通过焦磷酸测序进行了复制，并与大脑中的表达差异相关。CYP2E1 处的甲基化与 DMR 内的 ASD 诊断和基因型均相关。相比之下，IRS2 处的甲基化不受 DMR 内基因型的影响，但受受孕前母亲产前维生素使用的影响。因此，这项研究在胎盘上确定了两个潜在的有用的 ASD 早期表观遗传标记。
