Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes. We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS. Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status. The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited. Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

中文翻译：

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胎盘-大脑轴的证据：多组学核聚集预测极早产儿的智力和社交障碍


极度早产的儿童出现智力和社交障碍的风险较高，包括自闭症谱系障碍 (ASD)。越来越多的证据表明胎盘在产前发育规划中发挥着关键作用，这表明胎盘可能在一定程度上有助于神经发育结果的起源。我们检查了胎盘转录组和表观基因组谱之间的关联，并评估了 379 名来自极低胎龄新生儿 (ELGAN) 队列的儿童在 10 岁时预测智力和社交障碍的能力。智力能力（IQ）和社会功能的评估分别通过差异能力量表-II和社会反应量表（SRS）完成。检查 IQ 和 SRS 可以研究超出诊断标准的 ASD 风险，因为 IQ 和 SRS 是与 ASD 密切相关的连续测量。分别使用 Illumina Hiseq 2500、HTG EdgeSeq miRNA Whole Transcriptome Assay 和 Illumina EPIC/850 K array 检测全基因组 mRNA、CpG 甲基化和 miRNA。我们对胎盘 mRNA、miRNA 和 CpG 甲基化数据进行了全基因组差异分析。然后将这些分子特征整合起来，使用核聚合回归对 IQ 和 SRS 结果进行预测分析。我们最后检查了 ASD 与 IQ 和 SRS 的多组学预测部分之间的关​​联。在神经发育和胎盘组织组织中发挥重要作用的基因与智力和社交障碍有关。胎盘多组学的核聚合有力地预测了智力和社会功能，通过交叉验证分别解释了 SRS 和 IQ 分数约 8% 和 12% 的方差。 预测的样本内 SRS 和 IQ 显示与 ASD 病例对照状态存在显着的正相关和负相关。 ELGAN 队列包括早产儿，一般化可能会受到与低胎龄相关的未测量的混杂因素的影响。尽管样本量 (N = 49) 和可用样本外胎盘数据集的范围有限，但我们对预测模型进行了外部验证。值得进一步验证模型。聚合分子数据类型内部和之间的生物标志物的信息可以改善对极早产儿的社交和智力等复杂特征的预测，这表明胎盘-大脑轴内的特征可能是全基因的。