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; 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

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^*

^*Corresponding author for this work

University of Exeter
The Sahlgrenska Academy at the University of Gothenburg
Norwegian Institute of Public Health
Bergen University Medical School
Statens Serum Institut
Cincinnati Children's Hospital Medical Center
University of Cincinnati
University of Oslo
University of Queensland
Norwegian University of Science and Technology
University of Bristol
University of Copenhagen
Aarhus University
University of Oulu
Lund University (Malmö)
University of Helsinki
University of Newcastle
Hunter Medical Research Institute
Copenhagen University Hospital (Nordvest)
Methods and Analysis
University of Dundee School of Medicine
University of Edinburgh
University of the Basque Country
Biobizkaia Health Research Institute
Centro de Investigación Biomédica en Red (CIBER)
Université de Sherbrooke
University of Eastern Finland
Icahn School of Medicine at Mount Sinai
Oslo University Hospital
Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Saguenay–Lac-St-Jean—Hôpital Universitaire de Chicoutimi
The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Haukeland University Hospital
Imperial College London
Aarhus University Hospital
University of Valencia
FISABIO
Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP)
Center for Genomics and Personalized Medicine (CGPM)
National Institute for Health and Welfare
University of Southern Denmark
Aalborg University
Sjællands Universitetshospital
University of Michigan, Ann Arbor
Rigshospitalet
Oulu University Hospital
Kuopio University Hospital
the Capital Region of Denmark
Barcelona Institute for Global Health (ISGlobal)
Pompeu Fabra University
Danish Cancer Institute
Stanford University School of Medicine
MRC Integrative Epidemiology Unit at the University of Bristol
MRC Centre for Environment and Health
Harvard Pilgrim Health Care Institute
Massachusetts General Hospital
McGill University

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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.

Original language	English
Pages (from-to)	1807-1819
Number of pages	13
Journal	Nature Genetics
Volume	55
Issue number	11
DOIs	https://doi.org/10.1038/s41588-023-01520-w
Publication status	Published - Nov 2023

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growthFinal published version, 12.8 MBLicence: CC BY

Cite this

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. 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

@article{297fbb1e66644929982435d34dc8fc54,

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.",

author = "Beaumont, \{Robin N.\} and Christopher Flatley and Marc Vaudel and Xiaoping Wu and Jing Chen and Moen, \{Gunn Helen\} and Line Skotte and {\O}yvind Helgeland and Pol Sol{\'e}-Navais and Karina Banasik and Clara Albi{\~n}ana and Justiina Ronkainen and Jo{\~a}o Fadista and Stinson, \{Sara Elizabeth\} and Katerina Trajanoska and Wang, \{Carol A.\} and David Westergaard and Sundararajan Srinivasan and Carlos S{\'a}nchez-Soriano and Bilbao, \{Jose Ramon\} and Catherine Allard and Marika Groleau and Teemu Kuulasmaa and Leirer, \{Daniel J.\} and Fr{\'e}d{\'e}rique White and Jacques, \{Pierre {\'E}tienne\} and Haoxiang Cheng and Ke Hao and Andreassen, \{Ole A.\} and {\AA}svold, \{Bj{\o}rn Olav\} and Mustafa Atalay and Laxmi Bhatta and Luigi Bouchard and Brumpton, \{Ben Michael\} and S{\o}ren Brunak and Jonas Bybjerg-Grauholm and Cathrine Ebbing and Paul Elliott and Line Engelbrechtsen and Christian Erikstrup and Marisa Estarlich and Stephen Franks and Romy Gaillard and Frank Geller and Jakob Grove and Hougaard, \{David M.\} and Eero Kajantie and Morgen, \{Camilla S.\} and Nohr, \{Ellen A.\} and Mette Nyegaard and Palmer, \{Colin N.A.\} and Pedersen, \{Ole Birger\} and Fernando Rivadeneira and Sylvain Sebert and Shields, \{Beverley M.\} and Camilla Stoltenberg and Ida Surakka and Th{\o}rner, \{Lise Wegner\} and Henrik Ullum and Marja Vaarasmaki and Vilhjalmsson, \{Bjarni J.\} and Willer, \{Cristen J.\} and Lakka, \{Timo A.\} and Dorte Gybel-Brask and Mariona Bustamante and Torben Hansen and Pearson, \{Ewan R.\} and Reynolds, \{Rebecca M.\} and Ostrowski, \{Sisse R.\} and Pennell, \{Craig E.\} and Jaddoe, \{Vincent W.V.\} and Felix, \{Janine F.\} and Hattersley, \{Andrew T.\} and Mads Melbye and Lawlor, \{Deborah A.\} and Kristian Hveem and Thomas Werge and Nielsen, \{Henriette Svarre\} and Per Magnus and Evans, \{David M.\} and Bo Jacobsson and J{\"a}rvelin, \{Marjo Riitta\} and Ge Zhang and Hivert, \{Marie France\} and Stefan Johansson and Freathy, \{Rachel M.\} and Bjarke Feenstra and Nj{\o}lstad, \{P{\aa}l R.\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = nov,

doi = "10.1038/s41588-023-01520-w",

language = "English",

volume = "55",

pages = "1807--1819",

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issn = "1061-4036",

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Beaumont, RN, Flatley, C, Vaudel, M, Wu, X, Chen, J, Moen, GH, 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, PÉ, 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, MR, Zhang, G, Hivert, MF, 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 - 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

Y1 - 2023/11

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.

UR - https://www.scopus.com/pages/publications/85173791824

U2 - 10.1038/s41588-023-01520-w

DO - 10.1038/s41588-023-01520-w

M3 - Article

C2 - 37798380

AN - SCOPUS:85173791824

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

Abstract

Bibliographical note

UN SDGs

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