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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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-Moller, 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, Oyvind; 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.; Njolstad, Pal 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.; Vaudel, Marc; Weedon, Michael N.; Willemsen, Gonneke; Wood, Andrew R.; Yaghootkar, Hanieh; Muglia, Louis J.; Bartels, Meike; Relton, Caroline L.; Pennell, Craig E.; Chatzi, Leda; Estivill, Xavier; Holloway, John W.; Boomsma, Dorret I.; Montgomery, Grant W.; Murabito, Joanne M.; Spector, Tim D.; Power, Christine; Jarvelin, Marjo-Ritta; Bisgaard, Hans; Grant, Struan F. A.; Sørensen, Thorkild I. A.; Jaddoe, Vincent W.; Jacobsson, Bo; Melbye, Mads; McCarthy, Mark I.; Hattersley, Andrew T.; Hayes, M. Geoffrey; Frayling, Timothy M.; Hivert, Marie-France; Felix, Janine F.; Hypponen, Elina; Lowe, William L., Jr.; Evans, David M.; Lawlor, Debbie A.; Feenstra, Bjarke; Freathy, Rachel M.

In: Human Molecular Genetics, Vol. 27, No. 4, 2018, p. 742-756.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Beaumont, RN, Warrington, NM, Cavadino, A, Tyrrell, J, Nodzenski, M, Horikoshi, M, Geller, F, Myhre, R, Richmond, RC, Paternoster, L, Bradfield, JP, Kreiner-Moller, 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, O, Hocher, B, Hofman, A, Inskip, HM, Jones, SE, Kogevinas, M, Lind, PA, Marullo, L, Medland, SE, Murray, A, Murray, JC, Njolstad, PR, Nohr, EA, Reichetzeder, C, Ring, SM, Ruth, KS, Santa-Marina, L, Scholtens, DM, Sebert, S, Sengpiel, V, Tuke, MA, Vaudel, M, Weedon, MN, Willemsen, G, Wood, AR, Yaghootkar, H, Muglia, LJ, Bartels, M, Relton, CL, Pennell, CE, Chatzi, L, Estivill, X, Holloway, JW, Boomsma, DI, Montgomery, GW, Murabito, JM, Spector, TD, Power, C, Jarvelin, M-R, Bisgaard, H, Grant, SFA, Sørensen, TIA, Jaddoe, VW, Jacobsson, B, Melbye, M, McCarthy, MI, Hattersley, AT, Hayes, MG, Frayling, TM, Hivert, M-F, Felix, JF, Hypponen, E, Lowe, WLJ, Evans, DM, Lawlor, DA, Feenstra, B & Freathy, RM 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

APA

Beaumont, R. N., Warrington, N. M., Cavadino, A., Tyrrell, J., Nodzenski, M., Horikoshi, M., Geller, F., Myhre, R., Richmond, R. C., Paternoster, L., Bradfield, J. P., Kreiner-Moller, E., Huikari, V., Metrustry, S., Lunetta, K. L., Painter, J. N., Hottenga, J-J., Allard, C., Barton, S. J., ... Freathy, R. M. (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

Vancouver

Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M et al. 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. 2018;27(4):742-756. https://doi.org/10.1093/hmg/ddx429

Author

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-Moller, 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, Oyvind ; 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. ; Njolstad, Pal 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. ; Vaudel, Marc ; Weedon, Michael N. ; Willemsen, Gonneke ; Wood, Andrew R. ; Yaghootkar, Hanieh ; Muglia, Louis J. ; Bartels, Meike ; Relton, Caroline L. ; Pennell, Craig E. ; Chatzi, Leda ; Estivill, Xavier ; Holloway, John W. ; Boomsma, Dorret I. ; Montgomery, Grant W. ; Murabito, Joanne M. ; Spector, Tim D. ; Power, Christine ; Jarvelin, Marjo-Ritta ; Bisgaard, Hans ; Grant, Struan F. A. ; Sørensen, Thorkild I. A. ; Jaddoe, Vincent W. ; Jacobsson, Bo ; Melbye, Mads ; McCarthy, Mark I. ; Hattersley, Andrew T. ; Hayes, M. Geoffrey ; Frayling, Timothy M. ; Hivert, Marie-France ; Felix, Janine F. ; Hypponen, Elina ; Lowe, William L., Jr. ; Evans, David M. ; Lawlor, Debbie A. ; Feenstra, Bjarke ; Freathy, Rachel M. / 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.

Bibtex

@article{fccc107f82514236bd938e20b01adffc,
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. ",
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-Moller 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 Oyvind 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 Njolstad, {Pal 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 Marc Vaudel and Weedon, {Michael N.} and Gonneke Willemsen and Wood, {Andrew R.} and Hanieh Yaghootkar and Muglia, {Louis J.} and Meike Bartels and Relton, {Caroline L.} and Pennell, {Craig E.} and Leda Chatzi and Xavier Estivill and Holloway, {John W.} and Boomsma, {Dorret I.} and Montgomery, {Grant W.} and Murabito, {Joanne M.} and Spector, {Tim D.} and Christine Power and Marjo-Ritta Jarvelin and Hans Bisgaard and Grant, {Struan F. A.} and S{\o}rensen, {Thorkild I. A.} and Jaddoe, {Vincent W.} and Bo Jacobsson and Mads Melbye and McCarthy, {Mark I.} and Hattersley, {Andrew T.} and Hayes, {M. Geoffrey} and Frayling, {Timothy M.} and Marie-France Hivert and Felix, {Janine F.} and Elina Hypponen and Lowe, {William L., Jr.} and Evans, {David M.} and Lawlor, {Debbie A.} and Bjarke Feenstra and Freathy, {Rachel M.}",
year = "2018",
doi = "10.1093/hmg/ddx429",
language = "English",
volume = "27",
pages = "742--756",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "4",

}

RIS

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-Moller, 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, Oyvind

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 - Njolstad, Pal 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 - Vaudel, Marc

AU - Weedon, Michael N.

AU - Willemsen, Gonneke

AU - Wood, Andrew R.

AU - Yaghootkar, Hanieh

AU - Muglia, Louis J.

AU - Bartels, Meike

AU - Relton, Caroline L.

AU - Pennell, Craig E.

AU - Chatzi, Leda

AU - Estivill, Xavier

AU - Holloway, John W.

AU - Boomsma, Dorret I.

AU - Montgomery, Grant W.

AU - Murabito, Joanne M.

AU - Spector, Tim D.

AU - Power, Christine

AU - Jarvelin, Marjo-Ritta

AU - Bisgaard, Hans

AU - Grant, Struan F. A.

AU - Sørensen, Thorkild I. A.

AU - Jaddoe, Vincent W.

AU - Jacobsson, Bo

AU - Melbye, Mads

AU - McCarthy, Mark I.

AU - Hattersley, Andrew T.

AU - Hayes, M. Geoffrey

AU - Frayling, Timothy M.

AU - Hivert, Marie-France

AU - Felix, Janine F.

AU - Hypponen, Elina

AU - Lowe, William L., Jr.

AU - Evans, David M.

AU - Lawlor, Debbie A.

AU - Feenstra, Bjarke

AU - Freathy, Rachel M.

PY - 2018

Y1 - 2018

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.

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 -

ID: 209699201