Cell-free DNA fragmentomics for preeclampsia risk assessment

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder that could lead to serious maternal and fetal complications, yet early identification of women at risk remains challenging because reliable biomarkers are limited. Here we show that generating relatively stable cell-free DNA (cfDNA) fragmentomic metrics, including transcription start site (TSS) coverage, TSS score, and Gini coefficient, required 600 million whole-genome sequencing reads of plasma cfDNA. These metrics exhibited observable differences among genes with varying expression levels in blood cells and placental tissues. In a cohort of 1,058 pregnant women, cfDNA fragmentomics could distinguish pregnancies that subsequently developed PE. When integrated with maternal risk factors, predictive models in two independent test sets achieved mean area under the curves of 0.903 and 0.850 for early-onset and late-onset PE, respectively, with sensitivities of 0.731 and 0.607 at a 10% false positive rate. Importantly, these models also performed well in samples collected before or at 16 weeks of gestation, supporting the potential of cfDNA fragmentomics in early PE risk assessment.