Disentangling Maternal and Fetal Genetic Contributions to Preeclampsia

Abstract

Hypertensive disorders of pregnancy are a leading cause of maternal and fetal morbidity and mortality, with preeclampsia (PE) affecting [~]5% of pregnancies worldwide. Both maternal and fetal genomes influence PE risk, but their relative contributions remain unclear. We conducted a meta-analysis of genome-wide association studies assessing maternal and fetal genetic effects on PE, including 401,597 maternal and 435,076 fetal samples. We identified 27 independent PE-associated variants, comprising 12 novel and 3 fetal-specific loci. Maternal and fetal genetic effects were independent, potentially reflecting opposing selective pressures on maternal versus fetal determinants of PE. Most heritable risk arose from maternal variants linked to blood pressure regulation, adiposity, and immune tolerance. Causality analyses supported roles of maternal body mass index and lipid levels in PE susceptibility. In contrast, fetal factors predisposing to PE were associated with increased risk of psychiatric disorders in adulthood, but positive effects on reproductive success. Collectively, these findings delineate distinct maternal and fetal genetic architectures underlying PE and highlight divergent biological pathways contributing to PE risk.