Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage

David Westergaard; Valgerður Steinthórsdóttir; Lilja Stefánsdóttir; Palle Duun Rohde; Xiaoping Wu; Frank Geller; Jaakko S. Tyrmi; Aki Samuli Havulinna; Pol Solé-Navais; Christopher J. Flatley; Sisse Rye Ostrowski; Ole Birger Pedersen; Christian Erikstrup; Erik Sørensen; Christina Mikkelsen; Mie Topholm Brun; Bitten Aagaard Jensen; Thorsten Brodersen; Henrik Ullum; FinnGen; Per Minor Magnus; Ole A. Andreassen; Pål R. Njølstad; Astrid Marie Kolte; Lone Krebs; Mette Nyegaard; Thomas Folkmann Hansen; Bjarke Feenstra; Mark J. Daly; Cecilia M. Lindgren

doi:10.1101/2023.08.10.23293932

Genetic & Genomic MedicinemedRxivAug 10, 2023

Preprint

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage

David Westergaard iD, Valgerður Steinthórsdóttir iD, Lilja Stefánsdóttir iD, Palle Duun Rohde iD, Xiaoping Wu iD, Frank Geller iD, Jaakko S. Tyrmi iD, Aki Samuli Havulinna iD, Pol Solé-Navais iD, Christopher J. Flatley iD, Sisse Rye Ostrowski iD, Ole Birger Pedersen iD, Christian Erikstrup iD, Erik Sørensen iD, Christina Mikkelsen iD, Mie Topholm Brun, Bitten Aagaard Jensen, Thorsten Brodersen iD, Henrik Ullum iD, FinnGen iD, Per Minor Magnus iD, Ole A. Andreassen iD, Pål R. Njølstad iD, Astrid Marie Kolte iD, Lone Krebs iD, , Henriette Svarre Nielsen iD

Abstract

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.

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