Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia

BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. METHODS: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. RESULTS: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1, SH2B3, SERPINE2, RGS18, PZP, NOTUM, METAP1, MANEA, jun-D, GDF15 [growth/differentiation factor 15], FGL1, FGF5, FES, APOBR, ANP, ALDH-E2, ADAMTS13, and 3MG), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. CONCLUSIONS: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.