SUMMARY/ABSTRACT A substantial proportion of postnatal health, including childhood obesity and metabolic disease, is programmed in utero during fetal development. While birthweight has been linked to these outcomes, it may be only a proxy reflecting a complex interplay of genetics and environment that defines a common etiology between birthweight and later life health, and which defines the Developmental Origins of Heath and Disease (DOHaD) hypothesis. Supporting this hypothesis are a number of large, genome-wide association studies (GWAS) that have identified genetic variants associated with early life outcomes, such as birthweight and childhood obesity, body mass index and adiposity, and have demonstrated that these same variants can also impact adult cardiovascular traits and disease. Thus, early intervention, either through identifying at-risk population and/or targeting functional variations induced by genetic and environmental factors, could be highly effective in reducing overall disease burden. Our team spearheaded the placental research suggesting that the placenta may be the critical organ for much of childhood health programming. This proposal is framed on the hypothesis that the functional genome of a placenta acts as a critical and unique mediator of the in utero environment (both genetic and non-genetic) to influence birthweight and program postnatal growth and development, and such effects may occur in particular cellular components of the placenta. Leveraging the resources of three well-characterized and diverse birth cohorts in the US, we propose a rigorous integrative genomics and systems biology investigation to demonstrate the causal, mechanistic role of the placenta in postnatal health programming using state-of-the-art, post-GWAS, functional genomic investigations, including innovative use of single-nucleus RNA sequencing technology and molecular quantitative trait loci analyses (molQTL). We will build a comprehensive molecular atlas of human term placenta to identify functional molecular features that mediate birthweight GWAS hits as well as those independent of genetics, and we will build a placental transcriptomic atlas at cellular resolution to improve mechanistic understanding of the role of the placenta at the single cell level. Furthermore, we will examine prospective associations of the birthweight- related molecular features in placenta with growth trajectory, childhood obesity, BMI, and adiposity at age 5 as a model of the placenta’s role in long-term health programming. This project aligns with the research priorities of Pregnancy and Perinatology Branch of the NICHD, in defining “molecular biology processes involved in normal and abnormal placentation” as well as “genetic and epigenetic factors that adversely affect pregnancy outcomes”. Results from our study will pave the way for the development of placenta-based biomarkers to be assessed at birth for prospective risk stratification into childhood so early inter...