Evidence for the Placenta-Brain Axis: Multi-Omic Kernel Aggregation Predicts Intellectual and Social Impairment in Children Born Extremely Preterm

Background: Children born extremely preterm are at heightened risk for intellectual and social impairment. There is increasing evidence for a key role of the placenta in prenatal neurodevelopmental programming, suggesting that the placenta serves as a role in the origins of neurodevelopmental outcomes. Methods: We examined associations between genomic and epigenomic profiles in the placenta 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 (DAS-II) and Social Responsiveness Scale (SRS), respectively. Genome-wide mRNA, CpG methylation and miRNA were assessed with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850K array, respectively. We conducted genome-wide differential mRNA/miRNA and epigenome-wide placenta analyses. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. Results: We found that genes with important roles in placenta angiogenesis and neural function were associated with intellectual and social impairment. Multi-omic predictions of intellectual and social function were strong, explaining approximately 10% and 12% of the variance in SRS and IQ scores via cross-validation, respectively. Conclusions: Our findings demonstrate that aggregating information from biomarkers within and between molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits influenced by the placenta-brain axis may be omnigenic.