The University of Southampton
University of Southampton Institutional Repository

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.
78b1b38f-c61b-4a44-ae34-914d4e3592f0
Warrington, Nicole M.
d02e0311-3a40-43fc-9a01-41e3e44043f5
Cavadino, Alana
ad47c5ff-9d8c-449a-94e9-d2bb388e34d2
Tyrrell, Jessica
b658e1a6-ec80-4abc-8f9f-c18dffbbc6cd
Nodzenski, Michael
a7ced121-72fd-41d2-988f-4491aa203bb6
Horikoshi, Momoko
d8c9eadb-1402-442a-be0c-1cd45be763bd
Geller, Frank
a16292f8-b3b8-4c00-9e38-0778e75cae68
Myhre, Ronny
ae0211e5-5ebb-41ec-b592-c172458e36a3
Richmond, Rebecca C.
d5b662f4-180c-4adb-9080-51a793a1bfcc
Paternoster, Lavinia
7ca9ff58-0663-4bd3-bd70-186b34fb92a3
Bradfield, Jonathan P.
77b34e30-9683-4405-ab7e-8edf1866e8e9
Kreiner-Møller, Eskil
f5dee93b-b9d3-441c-92b8-b67a7a18d59d
Huikari, Ville
2a8cd30c-dc8f-4655-a12d-b1db9318da7b
Metrustry, Sarah
0e48f38a-f53d-41bb-9d8b-e8035e2b7ab7
Lunetta, Kathryn L.
46b677df-f04a-4eb8-9ed4-08237003e918
Painter, Jodie N.
a8952967-0b3b-4c9a-8b34-641a856e7b45
Hottenga, Jouke-Jan
cd7f700a-47e0-40c7-b6a8-e702c735ce7a
Allard, Catherine
87d68743-1b47-464c-83c6-0cf3dc7269fa
Barton, Sheila J.
4f674382-ca0b-44ad-9670-e71a0b134ef0
Espinosa, Ana
b4cd7047-5f1e-45b5-ac74-7947acc2b56b
Marsh, Julie A.
eb7367ec-757a-4e1b-bfbf-7266180e3898
Potter, Catherine
cec5bed2-9a77-4ff4-9d5b-97ba533a9858
Zhang, Ge
57eb90b7-b182-4203-93a1-0a0be4227c34
Ang, Wei
fab41904-013a-41f3-af55-3081a2383a85
Berry, Diane J.
a624d6c2-49a2-4162-bab2-ed1641c61c51
Bouchard, Luigi
3dd607b6-bb30-4823-9aee-73286a425a83
Das, Shikta
6ffdd16e-71b1-4bef-96b0-5c517b42227c
Hakonarson, Hakon
2bbcbada-c11d-41b6-acbe-32e998c8f6c3
Heikkinen, Jani
2e532a4f-b670-4afc-9892-4636d73b2e97
Helgeland, Øyvind
75e570de-0c29-4435-9de4-79214fa252b7
Hocher, Berthold
af1564dc-8e48-4d01-8176-84970cb657d1
Hofman, Albert
19e6a48f-bef9-43bd-8c54-1b6057ead0bc
Inskip, Hazel M.
5fb4470a-9379-49b2-a533-9da8e61058b7
Jones, Samuel E.
72d87b24-37d8-49a5-a8b7-86e8fdb2f246
Kogevinas, Manolis
3d3864dd-6986-4aba-bdbc-2119664d9165
Lind, Penelope A.
16d70ba0-82fb-4a8c-879a-1a2daa48b1d2
Marullo, Letizia
3cd2faae-ca8f-4f10-85a9-15138ce0b2d1
Medland, Sarah E.
c1db8cd0-d80d-40d2-8daf-40a2589f28cd
Murray, Anna
2c3bf35c-26dd-427d-9673-ccbfa7f17e9a
Murray, Jeffrey C.
dfc09355-43b7-4a25-b038-f19b795f86cc
Njølstad, Pål R.
c97f3871-6135-4b38-aa15-902fb9596172
Nohr, Ellen A.
f2f79644-d9d9-4ef7-b9da-16997b5cd4a0
Reichetzeder, Christoph
5269a32a-0a99-4ee3-8799-ee4dd3f8d355
Ring, Susan M.
75bad926-3425-4723-8774-926e13e9c31c
Ruth, Katherine S.
c5f8ec94-1c63-488d-86bd-65b7c5460c20
Santa-Marina, Loreto
980ea53f-4932-48d6-b0cd-066570417e22
Scholtens, Denise M.
ba4a0ef3-230b-4851-ad94-93bf02c8c827
Sebert, Sylvain
d3f6c0f7-92b9-4959-a86c-9f7ad3346ee3
Sengpiel, Verena
2b1dc7ae-e98a-4ae8-9aa6-fc2617a52195
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Early Growth Genetics (EGG) Consortium
Beaumont, Robin N.
78b1b38f-c61b-4a44-ae34-914d4e3592f0
Warrington, Nicole M.
d02e0311-3a40-43fc-9a01-41e3e44043f5
Cavadino, Alana
ad47c5ff-9d8c-449a-94e9-d2bb388e34d2
Tyrrell, Jessica
b658e1a6-ec80-4abc-8f9f-c18dffbbc6cd
Nodzenski, Michael
a7ced121-72fd-41d2-988f-4491aa203bb6
Horikoshi, Momoko
d8c9eadb-1402-442a-be0c-1cd45be763bd
Geller, Frank
a16292f8-b3b8-4c00-9e38-0778e75cae68
Myhre, Ronny
ae0211e5-5ebb-41ec-b592-c172458e36a3
Richmond, Rebecca C.
d5b662f4-180c-4adb-9080-51a793a1bfcc
Paternoster, Lavinia
7ca9ff58-0663-4bd3-bd70-186b34fb92a3
Bradfield, Jonathan P.
77b34e30-9683-4405-ab7e-8edf1866e8e9
Kreiner-Møller, Eskil
f5dee93b-b9d3-441c-92b8-b67a7a18d59d
Huikari, Ville
2a8cd30c-dc8f-4655-a12d-b1db9318da7b
Metrustry, Sarah
0e48f38a-f53d-41bb-9d8b-e8035e2b7ab7
Lunetta, Kathryn L.
46b677df-f04a-4eb8-9ed4-08237003e918
Painter, Jodie N.
a8952967-0b3b-4c9a-8b34-641a856e7b45
Hottenga, Jouke-Jan
cd7f700a-47e0-40c7-b6a8-e702c735ce7a
Allard, Catherine
87d68743-1b47-464c-83c6-0cf3dc7269fa
Barton, Sheila J.
4f674382-ca0b-44ad-9670-e71a0b134ef0
Espinosa, Ana
b4cd7047-5f1e-45b5-ac74-7947acc2b56b
Marsh, Julie A.
eb7367ec-757a-4e1b-bfbf-7266180e3898
Potter, Catherine
cec5bed2-9a77-4ff4-9d5b-97ba533a9858
Zhang, Ge
57eb90b7-b182-4203-93a1-0a0be4227c34
Ang, Wei
fab41904-013a-41f3-af55-3081a2383a85
Berry, Diane J.
a624d6c2-49a2-4162-bab2-ed1641c61c51
Bouchard, Luigi
3dd607b6-bb30-4823-9aee-73286a425a83
Das, Shikta
6ffdd16e-71b1-4bef-96b0-5c517b42227c
Hakonarson, Hakon
2bbcbada-c11d-41b6-acbe-32e998c8f6c3
Heikkinen, Jani
2e532a4f-b670-4afc-9892-4636d73b2e97
Helgeland, Øyvind
75e570de-0c29-4435-9de4-79214fa252b7
Hocher, Berthold
af1564dc-8e48-4d01-8176-84970cb657d1
Hofman, Albert
19e6a48f-bef9-43bd-8c54-1b6057ead0bc
Inskip, Hazel M.
5fb4470a-9379-49b2-a533-9da8e61058b7
Jones, Samuel E.
72d87b24-37d8-49a5-a8b7-86e8fdb2f246
Kogevinas, Manolis
3d3864dd-6986-4aba-bdbc-2119664d9165
Lind, Penelope A.
16d70ba0-82fb-4a8c-879a-1a2daa48b1d2
Marullo, Letizia
3cd2faae-ca8f-4f10-85a9-15138ce0b2d1
Medland, Sarah E.
c1db8cd0-d80d-40d2-8daf-40a2589f28cd
Murray, Anna
2c3bf35c-26dd-427d-9673-ccbfa7f17e9a
Murray, Jeffrey C.
dfc09355-43b7-4a25-b038-f19b795f86cc
Njølstad, Pål R.
c97f3871-6135-4b38-aa15-902fb9596172
Nohr, Ellen A.
f2f79644-d9d9-4ef7-b9da-16997b5cd4a0
Reichetzeder, Christoph
5269a32a-0a99-4ee3-8799-ee4dd3f8d355
Ring, Susan M.
75bad926-3425-4723-8774-926e13e9c31c
Ruth, Katherine S.
c5f8ec94-1c63-488d-86bd-65b7c5460c20
Santa-Marina, Loreto
980ea53f-4932-48d6-b0cd-066570417e22
Scholtens, Denise M.
ba4a0ef3-230b-4851-ad94-93bf02c8c827
Sebert, Sylvain
d3f6c0f7-92b9-4959-a86c-9f7ad3346ee3
Sengpiel, Verena
2b1dc7ae-e98a-4ae8-9aa6-fc2617a52195
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a

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.

Text
main-text-EGG_Maternal_GWAS_BW_121217-changes-accepted - Accepted Manuscript
Download (527kB)
Text
ddx429_supp_data - Accepted Manuscript
Download (2MB)
Spreadsheet
ddx429_supp_tables - Accepted Manuscript
Download (49kB)
Image
Figure1 - Accepted Manuscript
Download (311kB)
Image
Figure2 - Accepted Manuscript
Download (58kB)
Image
Figure3 - Accepted Manuscript
Download (62kB)
Image
Figure4 - Accepted Manuscript
Download (9MB)
Text
10.1093hmgddx429 - Version of Record
Available under License Creative Commons Attribution.
Download (431kB)

Show all 8 downloads.

More information

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

Catalogue record

Date deposited: 15 Jan 2018 17:30
Last modified: 16 Mar 2024 06:06

Export record

Altmetrics

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×