Distal mediator-enriched, placental transcriptome-wide analyses illustrate the Developmental Origins of Health and Disease

As the master regulator of the intrauterine environment, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) but is understudied in relation to tissue-specific gene and trait regulation. We performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 health traits across 5 physiological categories, using gene expression models trained with multi-omic data from the Extremely Low Gestational Age Newborn Study (N = 272). At P < 2.5 x 10-6, we detected 248 gene-trait associations (GTAs) across 176 genes, mostly for metabolic and neonatal traits and enriched for cell growth and immunological pathways. Of these GTAs, 89 showed significant mediation through genetic variants distal to the gene, identifying potential targets for functional validation. Functional validation of a mediator gene (EPS15) in human placenta-derived JEG-3 trophoblasts resulted in increased expression of its predicted targets, SPATA13 and FAM214A, both associated with the trait of waist-hip ratio in TWAS. These results illustrate the profound health impacts of placental genetic and genomic regulation in developmental programming across the life course.