Abstract
As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P ; < ; 2.5times {10}^{-6}, we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.
Highlights
As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied
We conduct a series of distal mediator-enriched transcriptome-wide association studies (TWAS) for a variety of complex traits by integrating genome-wide association studies (GWAS) data with placental eQTL data from Extremely Low Gestational Age Newborn (ELGAN)
For each significant distal association, we identified a set of biomarkers that potentially affects transcription of the TWAS gene: a total of 9 regulatory protein-encoding genes (RPs) and 159 CpG sites across all 89 distal associations
Summary
As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course. Traditional methods for TWAS largely overlook genetic variants distal to genes of interest, ostensibly mediated through regulatory biomarkers, like transcription factors, miRNAs, or DNA methylation sites[18] May these distal biomarkers explain a significant portion of both gene expression heritability and trait heritability on the tissue-specific expression level[19,20], they may influence tissue-specific trait associations for individual genes. Owing to the strong interplay of regulatory elements in placental gene regulation, we sought to systematically characterize portions of gene expression that are influenced by these distal regulatory elements
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
