Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage

David Westergaard; Valgerdur Steinthorsdottir; Lilja Stefansdottir; Palle Duun Rohde; Xiaoping Wu; Frank Geller; Jaakko Tyrmi; Aki S Havulinna; Pol Solé-Navais; Christopher Flatley; Sisse Rye Ostrowski; Ole Birger Pedersen; Christian Erikstrup; Erik Sørensen; Christina Mikkelsen; Mie Topholm Bruun; Bitten Aagaard Jensen; Thorsten Brodersen; Henrik Ullum; Per Magnus; Ole A Andreassen; Pål R Njolstad; Astrid Marie Kolte; Lone Krebs; Mette Nyegaard; Thomas Folkmann Hansen; Bjarke Feenstra; 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; FinnGen

doi:10.1038/s41588-024-01839-y

Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage

David Westergaard, Valgerdur Steinthorsdottir, Lilja Stefansdottir, Palle Duun Rohde, Xiaoping Wu, Frank Geller, Jaakko Tyrmi, Aki S Havulinna, Pol Solé-Navais, Christopher Flatley, Sisse Rye Ostrowski, Ole Birger Pedersen, Christian Erikstrup, Erik Sørensen, Christina Mikkelsen, Mie Topholm Bruun, Bitten Aagaard Jensen, Thorsten Brodersen, Henrik Ullum, Per MagnusOle A Andreassen, Pål R Njolstad, Astrid Marie Kolte, Lone Krebs, Mette Nyegaard, Thomas Folkmann Hansen, Bjarke Feenstra, 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^*, FinnGen

^*Corresponding author af dette arbejde

1 Citationer (Scopus)

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 severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. 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. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	56
Udgave nummer	8
Sider (fra-til)	1597-1603
Antal sider	7
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-024-01839-y
Status	Udgivet - aug. 2024

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Westergaard, D., Steinthorsdottir, V., Stefansdottir, L., Rohde, P. D., Wu, X., Geller, F., Tyrmi, J., Havulinna, A. S., Solé-Navais, P., Flatley, C., Ostrowski, S. R., Pedersen, O. B., Erikstrup, C., Sørensen, E., Mikkelsen, C., Bruun, M. T., Aagaard Jensen, B., Brodersen, T., Ullum, H., ... FinnGen (2024). Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage. Nature Genetics, 56(8), 1597-1603. https://doi.org/10.1038/s41588-024-01839-y

Westergaard, D, Steinthorsdottir, V, Stefansdottir, L, Rohde, PD, Wu, X , Geller, F, Tyrmi, J, Havulinna, AS, Solé-Navais, P, Flatley, C, Ostrowski, SR, Pedersen, OB, Erikstrup, C, Sørensen, E , Mikkelsen, C, Bruun, MT, Aagaard Jensen, B, Brodersen, T, Ullum, H, Magnus, P, Andreassen, OA, Njolstad, PR, Kolte, AM, Krebs, L, Nyegaard, M, Hansen, TF, Feenstra, B, Daly, M, Lindgren, CM, Thorleifsson, G, Stefansson, OA, Sveinbjornsson, G, Gudbjartsson, DF, Thorsteinsdottir, U, Banasik, K, Jacobsson, B, Laisk, T, Laivuori, H, Stefansson, K, Brunak, S, Nielsen, HS & FinnGen 2024, 'Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage', Nature Genetics, bind 56, nr. 8, s. 1597-1603. https://doi.org/10.1038/s41588-024-01839-y

@article{627e1a03fe714be5a00b7087cfb84ea2,

title = "Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage",

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 severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. 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. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.",

keywords = "Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Postpartum Hemorrhage/genetics, Pregnancy, Receptors, Progesterone/genetics",

author = "David Westergaard and Valgerdur Steinthorsdottir and Lilja Stefansdottir and Rohde, {Palle Duun} and Xiaoping Wu and Frank Geller and Jaakko Tyrmi and Havulinna, {Aki S} and Pol Sol{\'e}-Navais and Christopher Flatley and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger} and Christian Erikstrup and Erik S{\o}rensen and Christina Mikkelsen and Bruun, {Mie Topholm} and {Aagaard Jensen}, Bitten and Thorsten Brodersen and Henrik Ullum and Per Magnus and Andreassen, {Ole A} and Njolstad, {P{\aa}l R} and Kolte, {Astrid Marie} and Lone Krebs and Mette Nyegaard and Hansen, {Thomas Folkmann} and Bjarke Feenstra and Mark Daly and Lindgren, {Cecilia M} and Gudmar Thorleifsson and Stefansson, {Olafur A} and Gardar Sveinbjornsson and Gudbjartsson, {Daniel F} and Unnur Thorsteinsdottir and Karina Banasik and Bo Jacobsson and Triin Laisk and Hannele Laivuori and Kari Stefansson and S{\o}ren Brunak and Nielsen, {Henriette Svarre} and FinnGen",

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year = "2024",

month = aug,

doi = "10.1038/s41588-024-01839-y",

language = "English",

volume = "56",

pages = "1597--1603",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage

AU - Westergaard, David

AU - Steinthorsdottir, Valgerdur

AU - Stefansdottir, Lilja

AU - Rohde, Palle Duun

AU - Wu, Xiaoping

AU - Geller, Frank

AU - Tyrmi, Jaakko

AU - Havulinna, Aki S

AU - Solé-Navais, Pol

AU - Flatley, Christopher

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger

AU - Erikstrup, Christian

AU - Sørensen, Erik

AU - Mikkelsen, Christina

AU - Bruun, Mie Topholm

AU - Aagaard Jensen, Bitten

AU - Brodersen, Thorsten

AU - Ullum, Henrik

AU - Magnus, Per

AU - Andreassen, Ole A

AU - Njolstad, Pål R

AU - Kolte, Astrid Marie

AU - Krebs, Lone

AU - Nyegaard, Mette

AU - Hansen, Thomas Folkmann

AU - Feenstra, Bjarke

AU - Daly, Mark

AU - Lindgren, Cecilia M

AU - Thorleifsson, Gudmar

AU - Stefansson, Olafur A

AU - Sveinbjornsson, Gardar

AU - Gudbjartsson, Daniel F

AU - Thorsteinsdottir, Unnur

AU - Banasik, Karina

AU - Jacobsson, Bo

AU - Laisk, Triin

AU - Laivuori, Hannele

AU - Stefansson, Kari

AU - Brunak, Søren

AU - Nielsen, Henriette Svarre

AU - FinnGen

PY - 2024/8

Y1 - 2024/8

N2 - 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 severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. 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. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.

AB - 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 severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. 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. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Postpartum Hemorrhage/genetics

KW - Pregnancy

KW - Receptors, Progesterone/genetics

UR - http://www.scopus.com/inward/record.url?scp=85206888169&partnerID=8YFLogxK

U2 - 10.1038/s41588-024-01839-y

DO - 10.1038/s41588-024-01839-y

M3 - Journal article

C2 - 39039282

SN - 1061-4036

VL - 56

SP - 1597

EP - 1603

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage

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