Pregnant women are at greater risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), because of their altered immunity and strained cardiovascular system. Emerging studies of placenta, embryos, and cerebral organoids suggest that fetal organs including brain could also be vulnerable to coronavirus disease 2019 (COVID-19). Additionally, a case study from Paris has reported transient neurological complications in neonates born to pregnant mothers. However, it remains poorly understood whether the fetal brain expresses cellular components that interact with Spike protein (S) of coronaviruses, which facilitates fusion of virus and host cell membrane and is the primary protein in viral entry. To address this question, we analyzed the expression of known (ACE2, TMPRSS2, and FURIN) and novel (ZDHHC5, GOLGA7, and ATP1A1) S protein interactors in publicly available fetal brain bulk and single cell RNA sequencing datasets. Bulk RNA sequencing analysis across multiple regions of fetal brain spanning 8 weeks post conception (wpc)−37wpc indicates that two of the known S protein interactors are expressed at low levels with median normalized gene expression values ranging from 0.08 to 0.06 (ACE2) and 0.01–0.02 (TMPRSS2). However, the third known S protein interactor FURIN is highly expressed (11.1–44.09) in fetal brain. Interestingly, all three novel S protein interactors are abundantly expressed throughout fetal brain development with median normalized gene expression values ranging from 20.38–21.60 (ZDHHC5), 92.47–68.35 (GOLGA7), and 65.45–194.5 (ATP1A1). Moreover, the peaks of expression of novel interactors is around 12–26wpc. Using publicly available single cell RNA sequencing datasets, we further show that novel S protein interactors show higher co-expression with neurons than with neural progenitors and astrocytes. These results suggest that even though two of the known S protein interactors are present at low levels in fetal brain, novel S protein interactors are abundantly present and could play a direct or indirect role in SARS-CoV-2 fetal brain pathogenesis, especially during the 2nd and 3rd trimesters of pregnancy.
Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. In discovery analysis, we tested the association of maternal DNA sequence variants with preeclampsia in 17,150 cases and 451,241 controls and with gestational hypertension in 8,961 cases and 184,925 controls using multi-ancestry meta-analysis. We identified 12 independent loci associated with preeclampsia/eclampsia, 7 of which are novel (including MTHFR-CLCN6, WNT3A, PGR, FLT1, and RGL3), and 7 loci associated with gestational hypertension. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development, and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external datasets, independent of first-trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.
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