Placental Cell Type Deconvolution Reveals That Cell Proportions Drive Preeclampsia Gene Expression Differences

Details

• Personal Author:
  Bakulski KM ; Campbell KA ; Colacino JA ; Dolinoy DC ; Domino SE ; Dou JF ; Elkin ER ; Goodrich JM ; Hammoud SS ; Loch-Caruso R ; Padmanabhan V ; Puttabyatappa M
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Epidemiology Genetics Occupational Health Pregnancy Safety Urogenital System
• Keywords:
  Gene Expression Genomics Reproductive Health
• ISSN:
  2399-3642
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Michigan ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  6
• NIOSHTIC Number:
  nn:20070606
• Citation:
  Commun Biol 2023 Mar; 6:264
• Contact Point Address:
  Kelly M. Bakulski, Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
• Email:
  bakulski@umich.edu
• Federal Fiscal Year:
  2023
• Performing Organization:
  University of Michigan, Ann Arbor
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Communications Biology
• End Date:
  20280630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1d1cae89e7cc5db7e9173d82417125ea4a0f86eae714fe10418719e4589a2f92f7d24056e561fe1593f34d99d6929fda343c0a3c8fd99823904b6f064873e4ec
• Download URL:
  https://stacks.cdc.gov/view/cdc/208785/cdc_208785_DS1.pdf
• File Type:
  [PDF - 3.03 MB ]