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Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics
Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Journal Article
0964-6906
742-756
Beaumont, Robin N.
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Warrington, Nicole M.
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Cavadino, Alana
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Tyrrell, Jessica
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Nodzenski, Michael
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Horikoshi, Momoko
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Geller, Frank
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Myhre, Ronny
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Richmond, Rebecca C.
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Paternoster, Lavinia
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Kreiner-Møller, Eskil
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Huikari, Ville
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Allard, Catherine
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Espinosa, Ana
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Ang, Wei
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Berry, Diane J.
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Bouchard, Luigi
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Das, Shikta
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Hakonarson, Hakon
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Heikkinen, Jani
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Hocher, Berthold
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Hofman, Albert
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Inskip, Hazel M.
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Jones, Samuel E.
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Kogevinas, Manolis
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Lind, Penelope A.
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Marullo, Letizia
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Medland, Sarah E.
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Murray, Anna
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Murray, Jeffrey C.
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Njølstad, Pål R.
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Nohr, Ellen A.
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Reichetzeder, Christoph
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Ring, Susan M.
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Ruth, Katherine S.
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Sengpiel, Verena
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Holloway, John W.
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Early Growth Genetics (EGG) Consortium
Beaumont, Robin N.
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Warrington, Nicole M.
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Cavadino, Alana
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Tyrrell, Jessica
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Nodzenski, Michael
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Horikoshi, Momoko
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Geller, Frank
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Myhre, Ronny
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Richmond, Rebecca C.
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Paternoster, Lavinia
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Bradfield, Jonathan P.
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Kreiner-Møller, Eskil
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Huikari, Ville
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Metrustry, Sarah
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Lunetta, Kathryn L.
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Hottenga, Jouke-Jan
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Allard, Catherine
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Barton, Sheila J.
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Espinosa, Ana
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Marsh, Julie A.
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Potter, Catherine
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Zhang, Ge
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Ang, Wei
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Berry, Diane J.
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Bouchard, Luigi
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Das, Shikta
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Hakonarson, Hakon
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Heikkinen, Jani
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Helgeland, Øyvind
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Hocher, Berthold
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Hofman, Albert
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Inskip, Hazel M.
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Jones, Samuel E.
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Kogevinas, Manolis
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Lind, Penelope A.
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Marullo, Letizia
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Medland, Sarah E.
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Murray, Anna
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Njølstad, Pål R.
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Reichetzeder, Christoph
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Ring, Susan M.
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Ruth, Katherine S.
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Sebert, Sylvain
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Sengpiel, Verena
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Holloway, John W.
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Beaumont, Robin N., Warrington, Nicole M., Cavadino, Alana, Tyrrell, Jessica, Nodzenski, Michael, Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Richmond, Rebecca C., Paternoster, Lavinia, Bradfield, Jonathan P., Kreiner-Møller, Eskil, Huikari, Ville, Metrustry, Sarah, Lunetta, Kathryn L., Painter, Jodie N., Hottenga, Jouke-Jan, Allard, Catherine, Barton, Sheila J., Espinosa, Ana, Marsh, Julie A., Potter, Catherine, Zhang, Ge, Ang, Wei, Berry, Diane J., Bouchard, Luigi, Das, Shikta, Hakonarson, Hakon, Heikkinen, Jani, Helgeland, Øyvind, Hocher, Berthold, Hofman, Albert, Inskip, Hazel M., Jones, Samuel E., Kogevinas, Manolis, Lind, Penelope A., Marullo, Letizia, Medland, Sarah E., Murray, Anna, Murray, Jeffrey C., Njølstad, Pål R., Nohr, Ellen A., Reichetzeder, Christoph, Ring, Susan M., Ruth, Katherine S., Santa-Marina, Loreto, Scholtens, Denise M., Sebert, Sylvain, Sengpiel, Verena and Holloway, John W. , Early Growth Genetics (EGG) Consortium (2018) Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Human Molecular Genetics, 27 (4), 742-756. (doi:10.1093/hmg/ddx429).

Record type: Article

Abstract

Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

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Accepted/In Press date: 15 December 2017
e-pub ahead of print date: 3 January 2018
Published date: 15 February 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 416936
URI: http://eprints.soton.ac.uk/id/eprint/416936
ISSN: 0964-6906
PURE UUID: 2a8925d8-5912-49a7-8ad3-1f787861dc6e
ORCID for Sheila J. Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Hazel M. Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 15 Jan 2018 17:30
Last modified: 11 May 2024 04:01

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Contributors

Author: Robin N. Beaumont
Author: Nicole M. Warrington
Author: Alana Cavadino
Author: Jessica Tyrrell
Author: Michael Nodzenski
Author: Momoko Horikoshi
Author: Frank Geller
Author: Ronny Myhre
Author: Rebecca C. Richmond
Author: Lavinia Paternoster
Author: Jonathan P. Bradfield
Author: Eskil Kreiner-Møller
Author: Ville Huikari
Author: Sarah Metrustry
Author: Kathryn L. Lunetta
Author: Jodie N. Painter
Author: Jouke-Jan Hottenga
Author: Catherine Allard
Author: Ana Espinosa
Author: Julie A. Marsh
Author: Catherine Potter
Author: Ge Zhang
Author: Wei Ang
Author: Diane J. Berry
Author: Luigi Bouchard
Author: Shikta Das
Author: Hakon Hakonarson
Author: Jani Heikkinen
Author: Øyvind Helgeland
Author: Berthold Hocher
Author: Albert Hofman
Author: Hazel M. Inskip ORCID iD
Author: Samuel E. Jones
Author: Manolis Kogevinas
Author: Penelope A. Lind
Author: Letizia Marullo
Author: Sarah E. Medland
Author: Anna Murray
Author: Jeffrey C. Murray
Author: Pål R. Njølstad
Author: Ellen A. Nohr
Author: Christoph Reichetzeder
Author: Susan M. Ring
Author: Katherine S. Ruth
Author: Loreto Santa-Marina
Author: Denise M. Scholtens
Author: Sylvain Sebert
Author: Verena Sengpiel
Corporate Author: Early Growth Genetics (EGG) Consortium

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