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 EspinosaJulie 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, Sylvain Sebert, Verena Sengpiel, Marcus A Tuke, Early Growth Genetics (EGG) Consortium

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Resumé

Genome-wide association studies of birth weight have focused on fetal genetics, whereas 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 < 5 × 10-8. 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 that 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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind27
Udgave nummer4
Sider (fra-til)742–756
ISSN0964-6906
DOI
StatusUdgivet - 15. feb. 2018

Fingeraftryk

Genome-Wide Association Study
Mothers
Single Nucleotide Polymorphism
Maternal Inheritance
Low Birth Weight Infant
Proxy
Cytochrome P-450 Enzyme System
Fasting
Fetus
Alleles

Bibliografisk note

© The Author(s) 2018. Published by Oxford University Press.

Citer dette

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 ; Sebert, Sylvain ; Sengpiel, Verena ; Tuke, Marcus A ; 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. I: Human Molecular Genetics. 2018 ; Bind 27, Nr. 4. s. 742–756.
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title = "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",
abstract = "Genome-wide association studies of birth weight have focused on fetal genetics, whereas 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 < 5 × 10-8. 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 that 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.",
keywords = "Actins/genetics, Alleles, Birth Weight/genetics, Cytochrome P-450 CYP3A/genetics, DNA-Binding Proteins/genetics, Female, Genetic Variation/genetics, Genome-Wide Association Study/methods, Genotype, Gestational Age, HMGA2 Protein/genetics, Humans, Kv1.3 Potassium Channel/genetics, Polymorphism, Single Nucleotide/genetics, Protein-Serine-Threonine Kinases/genetics, Proteins/genetics, Receptor, Melatonin, MT2/genetics, Trans-Activators/genetics, Transcription Factor 7-Like 2 Protein/genetics",
author = "Beaumont, {Robin N} and Warrington, {Nicole M} and Alana Cavadino and Jessica Tyrrell and Michael Nodzenski and Momoko Horikoshi and Frank Geller and Ronny Myhre and Richmond, {Rebecca C} and Lavinia Paternoster and Bradfield, {Jonathan P} and Eskil Kreiner-M{\o}ller and Ville Huikari and Sarah Metrustry and Lunetta, {Kathryn L} and Painter, {Jodie N} and Jouke-Jan Hottenga and Catherine Allard and Barton, {Sheila J} and Ana Espinosa and Marsh, {Julie A} and Catherine Potter and Ge Zhang and Wei Ang and Berry, {Diane J} and Luigi Bouchard and Shikta Das and Hakon Hakonarson and Jani Heikkinen and {\O}yvind Helgeland and Berthold Hocher and Albert Hofman and Inskip, {Hazel M} and Jones, {Samuel E} and Manolis Kogevinas and Lind, {Penelope A} and Letizia Marullo and Medland, {Sarah E} and Anna Murray and Murray, {Jeffrey C} and Nj{\o}lstad, {P{\aa}l R} and Nohr, {Ellen A} and Christoph Reichetzeder and Ring, {Susan M} and Ruth, {Katherine S} and Loreto Santa-Marina and Scholtens, {Denise M} and Sylvain Sebert and Verena Sengpiel and Tuke, {Marcus A} and {Early Growth Genetics (EGG) Consortium}",
note = "{\circledC} The Author(s) 2018. Published by Oxford University Press.",
year = "2018",
month = "2",
day = "15",
doi = "10.1093/hmg/ddx429",
language = "English",
volume = "27",
pages = "742–756",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Heinemann",
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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, Sebert, S, Sengpiel, V, Tuke, MA & 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, bind 27, nr. 4, s. 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; Sebert, Sylvain; Sengpiel, Verena; Tuke, Marcus A; Early Growth Genetics (EGG) Consortium.

I: Human Molecular Genetics, Bind 27, Nr. 4, 15.02.2018, s. 742–756.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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 - Sebert, Sylvain

AU - Sengpiel, Verena

AU - Tuke, Marcus A

AU - Early Growth Genetics (EGG) Consortium

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

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Genome-wide association studies of birth weight have focused on fetal genetics, whereas 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 < 5 × 10-8. 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 that 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 of birth weight have focused on fetal genetics, whereas 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 < 5 × 10-8. 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 that 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 - Actins/genetics

KW - Alleles

KW - Birth Weight/genetics

KW - Cytochrome P-450 CYP3A/genetics

KW - DNA-Binding Proteins/genetics

KW - Female

KW - Genetic Variation/genetics

KW - Genome-Wide Association Study/methods

KW - Genotype

KW - Gestational Age

KW - HMGA2 Protein/genetics

KW - Humans

KW - Kv1.3 Potassium Channel/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Protein-Serine-Threonine Kinases/genetics

KW - Proteins/genetics

KW - Receptor, Melatonin, MT2/genetics

KW - Trans-Activators/genetics

KW - Transcription Factor 7-Like 2 Protein/genetics

U2 - 10.1093/hmg/ddx429

DO - 10.1093/hmg/ddx429

M3 - Journal article

C2 - 29309628

VL - 27

SP - 742

EP - 756

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -