Pregnancy-associated bleeding and genetics: Five sequence variants in the myometrium and progesterone signaling pathway are associated with postpartum hemorrhage

David Westergaard, Valgerdur Steinthorsdottir, Lilja Stefansdottir, Palle Duun Rohde, Xiaoping Wu, Frank Geller, Jaakko Tyrmi, Aki S Havulinna, Pol Sole Navais, Christopher Flatley, Sisse Rye Ostrowski, Ole Birger Pedersen, Christian Erikstrup, Erik Sørensen, Christina Mikkelsen, Mie Topholm Brun, Bitten Aagaard Jensen, Thorsten Brodersen, Henrik Ullum, FinnGenDanish Blood Donor Study Genomic Consortium, Estonian Biobank Research Team, Nordic Collaboration for Womens and Reproductive Health, Per Magnus, Ole A Andreassen, Pål R Njolstad, Astrid Marie Kolte, Lone Krebs, Mette Nyegaard, Thomas Folkmann Hansen, Bjarke Fenstra, Mark Daly, Cecilia M Lindgren, Gudmar Thorleifsson, Olafur A Stefansson, Gardar Sveinbjornsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Karina Banasik, Bo Jacobsson, Triin Laisk, Hannele Laivuori, Kari Stefansson, Søren Brunak, Henriette Svarre Nielsen

Publikation: Working paper/PreprintPreprint


Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2, TBX3, and RAP2C/FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.
Antal sider51
StatusUdgivet - 15 aug. 2023


  • genetic and genomic medicine


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