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

The Early Growth Genetics (EGG) Consortium; 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; Romy Gaillard; Frank Geller; Jakob Grove; David M. Hougaard; Eero Kajantie; Camilla S. Morgen; Ellen A. Nohr; Mette Nyegaard; Colin N. A. Palmer; Ole Birger Pedersen; Fernando Rivadeneira; Sylvain Sebert; Beverley M. Shields; Camilla Stoltenberg; Ida Surakka; Lise Wegner Thørner; Henrik Ullum; Marja Vaarasmaki; Bjarni J. Vilhjalmsson; Cristen J. Willer; Timo A. Lakka; Dorte Gybel-Brask; Mariona Bustamante; Torben Hansen; Ewan R. Pearson; Rebecca M. Reynolds; Sisse R. Ostrowski; Craig E. Pennell; Vincent W. V. Jaddoe; Janine F. Felix; Andrew T. Hattersley; Mads Melbye; Deborah A. Lawlor; Kristian Hveem; Thomas Werge; Henriette Svarre Nielsen; Per Magnus; David M. Evans; Bo Jacobsson; Marjo-Riitta Järvelin; Ge Zhang; Marie-France Hivert; Stefan Johansson; Rachel M. Freathy; Bjarke Feenstra; Pål R. 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

The Early Growth Genetics (EGG) Consortium, 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-SorianoJose 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, Romy Gaillard, Frank Geller, Jakob Grove, David M. Hougaard, Eero Kajantie, Camilla S. Morgen, Ellen A. Nohr, Mette Nyegaard, Colin N. A. Palmer, Ole Birger Pedersen, Fernando Rivadeneira, Sylvain Sebert, Beverley M. Shields, Camilla Stoltenberg, Ida Surakka, Lise Wegner Thørner, Henrik Ullum, Marja Vaarasmaki, Bjarni J. Vilhjalmsson, Cristen J. Willer, Timo A. Lakka, Dorte Gybel-Brask, Mariona Bustamante, Torben Hansen, Ewan R. Pearson, Rebecca M. Reynolds, Sisse R. Ostrowski, Craig E. Pennell, Vincent W. V. Jaddoe, Janine F. Felix, Andrew T. Hattersley, Mads Melbye, Deborah A. Lawlor, Kristian Hveem, Thomas Werge, Henriette Svarre Nielsen, Per Magnus, David M. Evans, Bo Jacobsson, Marjo-Riitta Järvelin, Ge Zhang, Marie-France Hivert, Stefan Johansson, Rachel M. Freathy, Bjarke Feenstra, Pål R. Njølstad

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1807-1819
Journal	Nature Genetics
Volume	55
Issue number	11
Early online date	5 Oct 2023
DOIs	https://doi.org/10.1038/s41588-023-01520-w
Publication status	Published - 1 Nov 2023

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The Early Growth Genetics (EGG) Consortium, 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., ... Njølstad, P. R. (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

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

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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The Early Growth Genetics (EGG) Consortium, 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, Gaillard, R, Geller, F, Grove, J, Hougaard, DM, Kajantie, E, Morgen, CS, Nohr, EA, Nyegaard, M, Palmer, CNA, Pedersen, OB, Rivadeneira, F, Sebert, S, Shields, BM, Stoltenberg, C, Surakka, I, Thørner, LW, Ullum, H, Vaarasmaki, M, Vilhjalmsson, BJ, Willer, CJ, Lakka, TA, Gybel-Brask, D, Bustamante, M, Hansen, T, Pearson, ER , Reynolds, RM, Ostrowski, SR, Pennell, CE, Jaddoe, VWV, Felix, JF, Hattersley, AT, Melbye, M, Lawlor, DA, Hveem, K, Werge, T, Nielsen, HS, Magnus, P, Evans, DM, Jacobsson, B, Järvelin, M-R, Zhang, G, Hivert, M-F, Johansson, S, Freathy, RM, Feenstra, B & Njølstad, PR 2023, 'Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth', Nature Genetics, vol. 55, no. 11, pp. 1807-1819. https://doi.org/10.1038/s41588-023-01520-w

TY - JOUR

T1 - Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

AU - The Early Growth Genetics (EGG) Consortium

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

AU - Franks, Stephen

AU - Gaillard, Romy

AU - Geller, Frank

AU - Grove, Jakob

AU - Hougaard, David M.

AU - Kajantie, Eero

AU - Morgen, Camilla S.

AU - Nohr, Ellen A.

AU - Nyegaard, Mette

AU - Palmer, Colin N. A.

AU - Pedersen, Ole Birger

AU - Rivadeneira, Fernando

AU - Sebert, Sylvain

AU - Shields, Beverley M.

AU - Stoltenberg, Camilla

AU - Surakka, Ida

AU - Thørner, Lise Wegner

AU - Ullum, Henrik

AU - Vaarasmaki, Marja

AU - Vilhjalmsson, Bjarni J.

AU - Willer, Cristen J.

AU - Lakka, Timo A.

AU - Gybel-Brask, Dorte

AU - Bustamante, Mariona

AU - Hansen, Torben

AU - Pearson, Ewan R.

AU - Reynolds, Rebecca M.

AU - Ostrowski, Sisse R.

AU - Pennell, Craig E.

AU - Jaddoe, Vincent W. V.

AU - Felix, Janine F.

AU - Hattersley, Andrew T.

AU - Melbye, Mads

AU - Lawlor, Deborah A.

AU - Hveem, Kristian

AU - Werge, Thomas

AU - Nielsen, Henriette Svarre

AU - Magnus, Per

AU - Evans, David M.

AU - Jacobsson, Bo

AU - Järvelin, Marjo-Riitta

AU - Zhang, Ge

AU - Hivert, Marie-France

AU - Johansson, Stefan

AU - Freathy, Rachel M.

AU - Feenstra, Bjarke

AU - Njølstad, Pål R.

PY - 2023/11/1

Y1 - 2023/11/1

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.

U2 - 10.1038/s41588-023-01520-w

DO - 10.1038/s41588-023-01520-w

M3 - Article

SN - 1061-4036

VL - 55

SP - 1807

EP - 1819

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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