Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals 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 Sole-Navais; Karina Banasik; Clara Albinana; Justina Kronkainen; Joao Fadista; Sara Elizabeth Stinson; Katerina Trajanoska; Carol A Wang; David Westergaard; Sundararajan Srinivasan; Carlos Sanchez Soriano; Jose Ramon Bilbao; Catherine  Allard; Marika Groleau; Teemu Kuulasmaa; Daniel J. Leirer; Frederique White; Pierre-Etienne Jacques; Haoxiang Cheng; Ke Hao; Ole A Andersen; 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; Kajantie Eero; Camilla S. Morgen; Ellen A Nohr; Mette Nyegaard; Colin N. A. Palmer; Ole Birger Pederson; Fernando Rivadeneira; Sylvain Sebert; Beverley M Shields; Camilla Stoltenberg; Ida Surakka; Lise Wegner Thorner; Henrik  Ullum; Marja Vaarasmaki; Bjarni J Vilhjálmsson; Cristen J. Willer; Timo A Lakka; Dorte Gybel-Brask; Mariona Bustamante; Torben Hansen; Ewan R. Pearson; Rebecca M Reynolds; Sisse Rye 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; Pal R. Njolstad

Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals 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 Sole-Navais, Karina Banasik, Clara Albinana, Justina Kronkainen, Joao Fadista, Sara Elizabeth Stinson, Katerina Trajanoska, Carol A Wang, David Westergaard, Sundararajan Srinivasan, Carlos Sanchez Soriano, Jose Ramon BilbaoCatherine Allard, Marika Groleau, Teemu Kuulasmaa, Daniel J. Leirer, Frederique White, Pierre-Etienne Jacques, Haoxiang Cheng, Ke Hao, Ole A Andersen, 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, Kajantie Eero, Camilla S. Morgen, Ellen A Nohr, Mette Nyegaard, Colin N. A. Palmer, Ole Birger Pederson, Fernando Rivadeneira, Sylvain Sebert, Beverley M Shields, Camilla Stoltenberg, Ida Surakka, Lise Wegner Thorner, Henrik Ullum, Marja Vaarasmaki, Bjarni J Vilhjálmsson, Cristen J. Willer, Timo A Lakka, Dorte Gybel-Brask, Mariona Bustamante, Torben Hansen, Ewan R. Pearson, Rebecca M Reynolds, Sisse Rye 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, Pal R. Njolstad

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Abstract / Description of output

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
Journal	Nature Genetics
Publication status	Published - 5 Oct 2023

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Placental Genetics paper accepted (1)Accepted author manuscript, 41.1 MB

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Beaumont, R. N., Flatley, C., Vaudel, M., Wu, X., Chen, J., Moen, G.-H., Skotte, L., Helgeland, Ø., Sole-Navais, P., Banasik, K., Albinana, C., Kronkainen, J., Fadista, J., Stinson, S. E., Trajanoska, K., Wang, C. A., Westergaard, D., Srinivasan, S., Sanchez Soriano, C., ... Njolstad, P. R. (2023). Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals distinct and shared genetic influences between placental and fetal growth. Nature Genetics.

@article{72e8d690c0dd4124aae146bd971ee2ad,

title = "Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals 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 Gunn-Helen Moen and Line Skotte and {\O}yvind Helgeland and Pol Sole-Navais and Karina Banasik and Clara Albinana and Justina Kronkainen and Joao Fadista and Stinson, {Sara Elizabeth} and Katerina Trajanoska and Wang, {Carol A} and David Westergaard and Sundararajan Srinivasan and {Sanchez Soriano}, Carlos and Bilbao, {Jose Ramon} and Catherine Allard and Marika Groleau and Teemu Kuulasmaa and Leirer, {Daniel J.} and Frederique White and Pierre-Etienne Jacques and Haoxiang Cheng and Ke Hao and Andersen, {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 Kajantie Eero and Morgen, {Camilla S.} and Nohr, {Ellen A} and Mette Nyegaard and Palmer, {Colin N. A.} and Pederson, {Ole Birger} and Fernando Rivadeneira and Sylvain Sebert and Shields, {Beverley M} and Camilla Stoltenberg and Ida Surakka and Thorner, {Lise Wegner} and Henrik Ullum and Marja Vaarasmaki and Vilhj{\'a}lmsson, {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 Rye} 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 Marjo-Riitta J{\"a}rvelin and Ge Zhang and Marie-France Hivert and Stefan Johansson and Freathy, {Rachel M} and Bjarke Feenstra and Njolstad, {Pal R.}",

year = "2023",

month = oct,

day = "5",

language = "English",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Beaumont, RN, Flatley, C, Vaudel, M, Wu, X, Chen, J, Moen, G-H, Skotte, L, Helgeland, Ø, Sole-Navais, P, Banasik, K, Albinana, C, Kronkainen, J, Fadista, J, Stinson, SE, Trajanoska, K, Wang, CA, Westergaard, D, Srinivasan, S, Sanchez Soriano, C, Bilbao, JR, Allard, C, Groleau, M, Kuulasmaa, T, Leirer, DJ, White, F, Jacques, P-E, Cheng, H, Hao, K, Andersen, 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, Eero, K, Morgen, CS, Nohr, EA, Nyegaard, M, Palmer, CNA, Pederson, OB, Rivadeneira, F, Sebert, S, Shields, BM, Stoltenberg, C, Surakka, I, Thorner, LW, Ullum, H, Vaarasmaki, M, Vilhjálmsson, 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 & Njolstad, PR 2023, 'Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals distinct and shared genetic influences between placental and fetal growth', Nature Genetics.

TY - JOUR

T1 - Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals 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 - Sole-Navais, Pol

AU - Banasik, Karina

AU - Albinana, Clara

AU - Kronkainen, Justina

AU - Fadista, Joao

AU - Stinson, Sara Elizabeth

AU - Trajanoska, Katerina

AU - Wang, Carol A

AU - Westergaard, David

AU - Srinivasan, Sundararajan

AU - Sanchez Soriano, Carlos

AU - Bilbao, Jose Ramon

AU - Allard, Catherine

AU - Groleau, Marika

AU - Kuulasmaa, Teemu

AU - Leirer, Daniel J.

AU - White, Frederique

AU - Jacques, Pierre-Etienne

AU - Cheng, Haoxiang

AU - Hao, Ke

AU - Andersen, 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 - Eero, Kajantie

AU - Morgen, Camilla S.

AU - Nohr, Ellen A

AU - Nyegaard, Mette

AU - Palmer, Colin N. A.

AU - Pederson, Ole Birger

AU - Rivadeneira, Fernando

AU - Sebert, Sylvain

AU - Shields, Beverley M

AU - Stoltenberg, Camilla

AU - Surakka, Ida

AU - Thorner, Lise Wegner

AU - Ullum, Henrik

AU - Vaarasmaki, Marja

AU - Vilhjálmsson, 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 Rye

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 - Njolstad, Pal R.

PY - 2023/10/5

Y1 - 2023/10/5

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.

M3 - Article

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals distinct and shared genetic influences between placental and fetal growth

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