Placental gene expression-based cell type deconvolution: Cell proportions drive preeclampsia gene expression differences

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 at term (n=15,532 cells). We deconvoluted eight published microarray case-control studies of preeclampsia (n=330). Deconvolution revealed excess extravillous trophoblasts and fewer mesenchymal cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (FDR<0.05) from 1,224 to 0, whereas pathway alterations exhibiting a metabolic adaptation to hypoxia were robust to cell type adjustment. Cellular composition explained 35.1% of the association between preeclampsia and FLT1 overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia that predicts previously observed bulk gene expression differences. Our deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.