Abstract
The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue (n = 9 biological replicates) at term (n = 40,494 cells). We deconvoluted eight published microarray case-control studies of preeclampsia (n = 173 controls, 157 cases). Preeclampsia was associated with excess extravillous trophoblasts and fewer mesenchymal and Hofbauer cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (log2 fold-change cutoff = 0.1, FDR < 0.05) from 1154 to 0, whereas downregulation of mitochondrial biogenesis, aerobic respiration, and ribosome biogenesis were robust to cell type adjustment, suggesting direct changes to these pathways. Cellular composition mediated a substantial proportion of the association between preeclampsia and FLT1 (37.8%, 95% CI [27.5%, 48.8%]), LEP (34.5%, 95% CI [26.0%, 44.9%]), and ENG (34.5%, 95% CI [25.0%, 45.3%]) overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia contributes to previously observed bulk gene expression differences. This deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.