AbstractPathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an expression signature of homeostatic inflammation in the term placenta and use expression quantitative trait loci (eQTLs) to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we carried out a phenome-wide association study, followed by mendelian randomization and identified protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth were also over-represented within the module. Our data support a model where disruption of placental homeostatic inflammation, following preterm birth or intra-amniotic infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals. Finally, we identify aspirin as a putative modulator of this homeostatic inflammatory signature.