Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Robin N Beaumont; Christopher Flatley; Marc Vaudel; Xiaoping Wu; Jing Chen; Gunn-Helen Moen; Line Skotte; Øyvind Helgeland; Pol Solé-Navais; Karina Banasik; Clara Albiñana; Justiina Ronkainen; João Fadista; Sara Elizabeth Stinson; Katerina Trajanoska; Carol A Wang; David Westergaard; Sundararajan Srinivasan; Carlos Sánchez-Soriano; Jose Ramon Bilbao; Catherine Allard; Marika Groleau; Teemu Kuulasmaa; Daniel J Leirer; Frédérique White; Pierre-Étienne Jacques; Haoxiang Cheng; Ke Hao; Ole A Andreassen; Bjørn Olav Åsvold; Mustafa Atalay; Laxmi Bhatta; Luigi Bouchard; Ben Michael Brumpton; Søren Brunak; Jonas Bybjerg-Grauholm; Cathrine Ebbing; Paul Elliott; Line Engelbrechtsen; Christian Erikstrup; Marisa Estarlich; Stephen Franks; Camilla S Morgen; Ole Birger Pedersen; Lise Wegner Thørner; Henrik Ullum; Torben Hansen; Sisse R Ostrowski; Thomas Werge; Henriette Svarre Nielsen; Early Growth Genetics (EGG) Consortium; Stefan Johansson; Rachel M Freathy; Bjarke Feenstra; Pål Njølstad

doi:10.1038/s41588-023-01520-w

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Robin N Beaumont, Christopher Flatley, Marc Vaudel, Xiaoping Wu, Jing Chen, Gunn-Helen Moen, Line Skotte, Øyvind Helgeland, Pol Solé-Navais, Karina Banasik, Clara Albiñana, Justiina Ronkainen, João Fadista, Sara Elizabeth Stinson, Katerina Trajanoska, Carol A Wang, David Westergaard, Sundararajan Srinivasan, Carlos Sánchez-Soriano, Jose Ramon BilbaoCatherine Allard, Marika Groleau, Teemu Kuulasmaa, Daniel J Leirer, Frédérique White, Pierre-Étienne Jacques, Haoxiang Cheng, Ke Hao, Ole A Andreassen, Bjørn Olav Åsvold, Mustafa Atalay, Laxmi Bhatta, Luigi Bouchard, Ben Michael Brumpton, Søren Brunak, Jonas Bybjerg-Grauholm, Cathrine Ebbing, Paul Elliott, Line Engelbrechtsen, Christian Erikstrup, Marisa Estarlich, Stephen Franks, Camilla S Morgen, Ole Birger Pedersen, Lise Wegner Thørner, Henrik Ullum, Torben Hansen, Sisse R Ostrowski, Thomas Werge, Henriette Svarre Nielsen, Early Growth Genetics (EGG) Consortium, Stefan Johansson^*, Rachel M Freathy^*, Bjarke Feenstra^*, Pål Njølstad^*

^*Corresponding author af dette arbejde

19 Citationer (Scopus)

Abstract

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	55
Udgave nummer	11
Sider (fra-til)	1807-1819
Antal sider	13
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-023-01520-w
Status	Udgivet - nov. 2023

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Beaumont, R. N., Flatley, C., Vaudel, M., Wu, X., Chen, J., Moen, G.-H., Skotte, L., Helgeland, Ø., Solé-Navais, P., Banasik, K., Albiñana, C., Ronkainen, J., Fadista, J., Stinson, S. E., Trajanoska, K., Wang, C. A., Westergaard, D., Srinivasan, S., Sánchez-Soriano, C., ... Njølstad, P. (2023). Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth. Nature Genetics, 55(11), 1807-1819. https://doi.org/10.1038/s41588-023-01520-w

Beaumont, RN, Flatley, C, Vaudel, M, Wu, X, Chen, J, Moen, G-H, Skotte, L, Helgeland, Ø, Solé-Navais, P, Banasik, K, Albiñana, C, Ronkainen, J, Fadista, J, Stinson, SE, Trajanoska, K, Wang, CA, Westergaard, D, Srinivasan, S, Sánchez-Soriano, C, Bilbao, JR, Allard, C, Groleau, M, Kuulasmaa, T, Leirer, DJ, White, F, Jacques, P-É, Cheng, H, Hao, K, Andreassen, OA, Åsvold, BO, Atalay, M, Bhatta, L, Bouchard, L, Brumpton, BM, Brunak, S, Bybjerg-Grauholm, J, Ebbing, C, Elliott, P, Engelbrechtsen, L, Erikstrup, C, Estarlich, M, Franks, S, Morgen, CS, Pedersen, OB, Thørner, LW, Ullum, H, Hansen, T, Ostrowski, SR , Werge, T , Nielsen, HS, Early Growth Genetics (EGG) Consortium, Johansson, S, Freathy, RM, Feenstra, B & Njølstad, P 2023, 'Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth', Nature Genetics, bind 55, nr. 11, s. 1807-1819. https://doi.org/10.1038/s41588-023-01520-w

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abstract = "A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.",

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AU - Beaumont, Robin N

AU - Flatley, Christopher

AU - Vaudel, Marc

AU - Wu, Xiaoping

AU - Chen, Jing

AU - Moen, Gunn-Helen

AU - Skotte, Line

AU - Helgeland, Øyvind

AU - Solé-Navais, Pol

AU - Banasik, Karina

AU - Albiñana, Clara

AU - Ronkainen, Justiina

AU - Fadista, João

AU - Stinson, Sara Elizabeth

AU - Trajanoska, Katerina

AU - Wang, Carol A

AU - Westergaard, David

AU - Srinivasan, Sundararajan

AU - Sánchez-Soriano, Carlos

AU - Bilbao, Jose Ramon

AU - Allard, Catherine

AU - Groleau, Marika

AU - Kuulasmaa, Teemu

AU - Leirer, Daniel J

AU - White, Frédérique

AU - Jacques, Pierre-Étienne

AU - Cheng, Haoxiang

AU - Hao, Ke

AU - Andreassen, Ole A

AU - Åsvold, Bjørn Olav

AU - Atalay, Mustafa

AU - Bhatta, Laxmi

AU - Bouchard, Luigi

AU - Brumpton, Ben Michael

AU - Brunak, Søren

AU - Bybjerg-Grauholm, Jonas

AU - Ebbing, Cathrine

AU - Elliott, Paul

AU - Engelbrechtsen, Line

AU - Erikstrup, Christian

AU - Estarlich, Marisa

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AU - Thørner, Lise Wegner

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AU - Ostrowski, Sisse R

AU - Werge, Thomas

AU - Nielsen, Henriette Svarre

AU - Early Growth Genetics (EGG) Consortium

AU - Johansson, Stefan

AU - Freathy, Rachel M

AU - Feenstra, Bjarke

AU - Njølstad, Pål

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N2 - A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

AB - A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

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KW - Female

KW - Fetal Development/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Insulin

KW - Male

KW - Placenta/metabolism

KW - Pregnancy

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DO - 10.1038/s41588-023-01520-w

M3 - Journal article

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SN - 1061-4036

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JO - Nature Genetics

JF - Nature Genetics

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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

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