Longitudinal multi-omics analysis of umbilical cord blood and childhood serum in Autism

Abstract

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.