Preeclampsia (PE), a gestational hypertensive disorder, ranks as the second leading cause of maternal mortality worldwide. While PE is considered a multifactorial disease, placental insufficiency is believed to drive its progression. To noninvasively study placental physiology related to adverse pregnancy outcomes (APOs) and predict these outcomes before symptom onset, we measured nine placental protein levels in first- and second-trimester serum samples from 2,352 nulliparous pregnant women in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) study. The proteins analyzed include VEGF, PlGF, ENG, sFlt-1, ADAM-12, PAPP-A, fβHCG, INHA, and AFP. Currently, little is known about the genetic variants contributing to the heritability of these proteins during pregnancy, and no studies have explored the causal relationships between early pregnancy proteins and gestational hypertensive disorders. Our study has three objectives. First, we conducted genome-wide association study (GWAS) of nine placental proteins in maternal serum during the first and second trimesters and the difference between time points to understand how genetics may influence placental proteins in early pregnancy. Second, we examined whether early pregnancy placental proteins are causal factors for PE and gestational hypertension (gHTN). Lastly, we investigated the causal relationship between PE/gHTN and long-term HTN. In conclusion, our study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization (MR) analyses demonstrated evidence of causal relationships between placental proteins, particularly ADAM-12, and gHTN, potentially informing prevention and treatment strategies. Our findings suggest that placental proteins like ADAM-12 could serve as biomarkers for postpartum HTN risk.

M.C.H. reports consulting fees from CRISPR Therapeutics; advisory board service for Miga Health; and grant support from Genentech (all unrelated to the present work).

Support for performing DNA extraction and GWAS from the Indiana University Grand Challenges Precision Diabetes project funding. D.M.H. was partially funded by R01HD101246 from the U.S. National Institutes of Health (NIH). M.C.H. was supported by K08HL166687 from the U.S. NIH and American Heart Association (940166, 979465). Original funding for nuMoM2b sample and data collection are noted in the study methods papers (HAAS et al. 2015, 2016).

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Nulliparous women with singleton pregnancies were recruited from hospitals affiliated with eight clinical centers: Case Western University; Columbia University; Indiana University; University of Pittsburgh; Northwestern University; University of California at Irvine; University of Pennsylvania; and University of Utah. The Data Coordinating and Analysis Center is RTI International. Each site's local governing Institutional Review Board(s) approved the protocol and procedures.

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The individual-level phenotype and genotype data have been reported earlier and are available upon request.