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

Robin N Beaumont, Nicole M Warrington, Alana Cavadino, Jessica Tyrrell, Michael Nodzenski, Momoko Horikoshi, Frank Geller, Ronny Myhre, Rebecca C Richmond, Lavinia Paternoster, Jonathan P Bradfield, Eskil Kreiner-Møller, Ville Huikari, Sarah Metrustry, Kathryn L Lunetta, Jodie N Painter, Jouke-Jan Hottenga, Catherine Allard, Sheila J Barton, Ana Espinosa & 31 others Julie A Marsh, Catherine Potter, Ge Zhang, Wei Ang, Diane J Berry, Luigi Bouchard, Shikta Das, Hakon Hakonarson, Jani Heikkinen, Øyvind Helgeland, Berthold Hocher, Albert Hofman, Hazel M Inskip, Samuel E Jones, Manolis Kogevinas, Penelope A Lind, Letizia Marullo, Sarah E Medland, Anna Murray, Jeffrey C Murray, Pål R Njølstad, Ellen A Nohr, Christoph Reichetzeder, Susan M Ring, Katherine S Ruth, Loreto Santa-Marina, Denise M Scholtens, Gonneke Willemsen, Meike Bartels, Dorret I Boomsma, Early Growth Genetics (EGG) Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)742-756
JournalHuman Molecular Genetics
Volume27
Issue number4
DOIs
Publication statusPublished - 1 Feb 2018

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Genome-Wide Association Study
Birth Weight
Mothers
Fetal Development
Single Nucleotide Polymorphism
Maternal Inheritance
Glucose
Gonadal Steroid Hormones
Low Birth Weight Infant
Proxy
Cytochrome P-450 Enzyme System
Fasting
Fetus
Alleles
Genotype
Blood Pressure
Morbidity
Mortality

Keywords

  • Journal Article

Cite this

Beaumont, R. N., Warrington, N. M., Cavadino, A., Tyrrell, J., Nodzenski, M., Horikoshi, M., ... 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. https://doi.org/10.1093/hmg/ddx429
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 ; Willemsen, Gonneke ; Bartels, Meike ; Boomsma, Dorret I ; Early Growth Genetics (EGG) Consortium. / 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. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 4. pp. 742-756.
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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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Beaumont, RN, Warrington, NM, Cavadino, A, Tyrrell, J, Nodzenski, M, Horikoshi, M, Geller, F, Myhre, R, Richmond, RC, Paternoster, L, Bradfield, JP, Kreiner-Møller, E, Huikari, V, Metrustry, S, Lunetta, KL, Painter, JN, Hottenga, J-J, Allard, C, Barton, SJ, Espinosa, A, Marsh, JA, Potter, C, Zhang, G, Ang, W, Berry, DJ, Bouchard, L, Das, S, Hakonarson, H, Heikkinen, J, Helgeland, Ø, Hocher, B, Hofman, A, Inskip, HM, Jones, SE, Kogevinas, M, Lind, PA, Marullo, L, Medland, SE, Murray, A, Murray, JC, Njølstad, PR, Nohr, EA, Reichetzeder, C, Ring, SM, Ruth, KS, Santa-Marina, L, Scholtens, DM, Willemsen, G, Bartels, M, Boomsma, DI & 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, vol. 27, no. 4, pp. 742-756. https://doi.org/10.1093/hmg/ddx429

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. / 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; Willemsen, Gonneke; Bartels, Meike; Boomsma, Dorret I; Early Growth Genetics (EGG) Consortium.

In: Human Molecular Genetics, Vol. 27, No. 4, 01.02.2018, p. 742-756.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - 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

AU - Beaumont, Robin N

AU - Warrington, Nicole M

AU - Cavadino, Alana

AU - Tyrrell, Jessica

AU - Nodzenski, Michael

AU - Horikoshi, Momoko

AU - Geller, Frank

AU - Myhre, Ronny

AU - Richmond, Rebecca C

AU - Paternoster, Lavinia

AU - Bradfield, Jonathan P

AU - Kreiner-Møller, Eskil

AU - Huikari, Ville

AU - Metrustry, Sarah

AU - Lunetta, Kathryn L

AU - Painter, Jodie N

AU - Hottenga, Jouke-Jan

AU - Allard, Catherine

AU - Barton, Sheila J

AU - Espinosa, Ana

AU - Marsh, Julie A

AU - Potter, Catherine

AU - Zhang, Ge

AU - Ang, Wei

AU - Berry, Diane J

AU - Bouchard, Luigi

AU - Das, Shikta

AU - Hakonarson, Hakon

AU - Heikkinen, Jani

AU - Helgeland, Øyvind

AU - Hocher, Berthold

AU - Hofman, Albert

AU - Inskip, Hazel M

AU - Jones, Samuel E

AU - Kogevinas, Manolis

AU - Lind, Penelope A

AU - Marullo, Letizia

AU - Medland, Sarah E

AU - Murray, Anna

AU - Murray, Jeffrey C

AU - Njølstad, Pål R

AU - Nohr, Ellen A

AU - Reichetzeder, Christoph

AU - Ring, Susan M

AU - Ruth, Katherine S

AU - Santa-Marina, Loreto

AU - Scholtens, Denise M

AU - Willemsen, Gonneke

AU - Bartels, Meike

AU - Boomsma, Dorret I

AU - Early Growth Genetics (EGG) Consortium

N1 - © The Author 2018. Published by Oxford University Press.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/hmg/ddx429

DO - 10.1093/hmg/ddx429

M3 - Article

VL - 27

SP - 742

EP - 756

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -