Noone Aisling, Dowling Kirsten, O'Boyle Daragh, Carter Michael, Golubeva Anna V, Scaife Caitriona, Bech Bodil H, Henriksen Tine B, Gallagher Louise, Mooney Catherine, Khashan Ali S, Murray Deirdre M, English Jane A
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
INFANT Research Centre, University College Cork, Cork, Ireland.
Mol Psychiatry. 2025 Sep 17. doi: 10.1038/s41380-025-03157-z.
There is considerable evidence implicating maternal immune activation (MIA) and cytokine dysregulation in the pathophysiology of Autism. However, cytokines, due to their lack of specificity are unlikely to translate clinically as prognostic biomarkers. Our aim was to explore the perinatal molecular pathways dysregulated in umbilical cord blood, which precede a diagnosis of childhood Autism, and ascertain whether these putative biomarkers persisted into pre-pubertal childhood. In a cohort of 2137 mother-infant dyads, we conducted a nested case-control study in the BASELINE Birth Cohort. Proteomic and metabolomic analysis was performed on cord blood plasma from 22 children diagnosed with Autism before age 5, and 44 neurotypical controls. In a clinical diagnostic follow-up between 7-10 years in the PiRAMiD Cohort, 24 children with Autism and 48 controls provided blood samples for molecular profiling. In cord blood, proteomics revealed altered glycolysis, selenium metabolism, oxygen transport, and complement signalling. Alterations in these protein pathways persisted into childhood, and dysregulation of GAPDH, SELENBP1, and BLVRB proteins were evident in both cord blood and in serum from pre-pubertal children with Autism. In cord blood, metabolomics analysis indicated Autism outcome was associated with reduced levels of circulating steroids and increased sulfate. We confirmed androstenedione was reduced in cord blood, in Autism cases in comparison to controls, however changes in androstenedione levels were not evident in serum from pre-pubertal children with Autism. Our findings were further corroborated using machine learning approaches, with an AUROC ranging from 0.82 to 0.85 for proteomic and metabolomic cord blood prediction models, respectively. Collectively, these findings confirm a cord blood molecular signature precedes the onset of Autism and has the potential to lead to prognostic biomarkers. Our integrative multi-omics analysis reveals materno-feto-placental molecular processes which potentially underpin Autism aetiology.
有大量证据表明母体免疫激活（MIA）和细胞因子失调与自闭症的病理生理学有关。然而，由于细胞因子缺乏特异性，它们不太可能作为临床预后生物标志物。我们的目的是探索在儿童自闭症诊断之前脐带血中失调的围产期分子途径，并确定这些假定的生物标志物是否持续到青春期前的儿童期。在2137对母婴二元组的队列中，我们在基线出生队列中进行了一项巢式病例对照研究。对22名5岁前被诊断为自闭症的儿童和44名神经典型对照的脐带血血浆进行了蛋白质组学和代谢组学分析。在PiRAMiD队列7至10岁的临床诊断随访中，24名自闭症儿童和48名对照提供了用于分子分析的血液样本。在脐带血中，蛋白质组学显示糖酵解、硒代谢、氧运输和补体信号传导发生改变。这些蛋白质途径的改变持续到儿童期，并且在自闭症青春期前儿童的脐带血和血清中，甘油醛-3-磷酸脱氢酶（GAPDH）、硒结合蛋白1（SELENBP1）和胆红素还原酶B（BLVRB）蛋白的失调都很明显。在脐带血中，代谢组学分析表明自闭症的结局与循环类固醇水平降低和硫酸盐增加有关。我们证实，与对照组相比，自闭症病例的脐带血中雄烯二酮减少，然而，自闭症青春期前儿童的血清中雄烯二酮水平的变化并不明显。我们的发现通过机器学习方法得到了进一步证实，蛋白质组学和代谢组学脐带血预测模型的曲线下面积（AUROC）分别为0.82至0.85。总的来说，这些发现证实了脐带血分子特征在自闭症发病之前就已存在，并且有可能产生预后生物标志物。我们的综合多组学分析揭示了可能是自闭症病因基础的母胎-胎盘分子过程。
