早产儿患有神经发育障碍的风险增加，包括自闭症谱系障碍（ASD）。胎盘是神经发育过程的关键调节因子，尽管精确的分子机制尚不清楚。在这里，我们采用多组学方法，识别出与在儿童早产出生时与ASD诊断相关的胎盘转录组和表观遗传修饰。在极低孕龄（ELGAN）队列中开展工作，我们假设炎性胎盘环境将预测10岁时的ASD诊断。将368名ELGAN（28名ASD患者和340名无ASD的孩子）之间的胎盘信使RNA (mRNA)表达、CpG甲基化和microRNA (miRNA)表达进行比较。共有111个基因显示与ASD相关的胎盘表达水平。在这些ASD相关基因中，包含了一个ASD调控复合物，其中关键基因预测了ASD病例状态。预测ASD病例状态的表达基因包括Ewing 肉瘤断点区域1（EWSR1）（OR: 6.57（95% CI: 2.34, 23.58））和邻近锌指结构域2A的Bromodomain（BAZ2A）（OR：0.12（95% CI：0.03,0.35））。此外，111个ASD相关基因中，9个（8.1％）与CpG甲基化水平有关联，而14个（12.6％）与miRNA表达水平有关联。在其中，LRR结合FLII交互蛋白1（LRRFIP1）被发现受CpG甲基化和miRNAs的控制，显示OR为0.42（95％ CI：0.17,0.95）。这些其中的基因，以及被识别出具有功能表观突变的其他基因，在免疫系统调节和炎症反应中起着关键作用。总之，利用多组学方法识别出与早产儿ASD发展相关的胎盘功能表观突变，为未来干预提供了途径。 ©2023InternationalSocietyforAutismResearch and WileyPeriodicalsLLC。

Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi-omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro-inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD-associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD-associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi-omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.© 2023 International Society for Autism Research and Wiley Periodicals LLC.