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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

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

  • 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 Â 10 À8 . 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 beenGenome-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 Â 10 À8 . 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.show moreshow less

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Author: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, Julie A. Marsh, Catherine Potter, Ge Zhang, Wei Ang, Diane J. Berry, Luigi Bouchard, Shikta Das, Hakon Hakonarson, Jani Heikkinen, Øyvind Helgeland, Berthold HocherORCiDGND, Albert Hofman, Hazel M. Inskip, Samuel E. Jones, Manolis Kogevinas, Penelope A. Lind, Letizia Marullo, Sarah E. Medland, Anna Murray, Jeffrey C. Murray, Pa ̊l R. Njølstad, Ellen A. Nohr, Christoph ReichetzederORCiDGND, Susan M. Ring, Katherine S. Ruth, Loreto Santa-Marina, Denise M. Scholtens, Sylvain Sebert, Verena Sengpiel, Marcus A. Tuke, Marc Vaudel, Michael N. Weedon, Gonneke Willemsen, Andrew R. Wood, Hanieh Yaghootkar, Louis J. Muglia, Meike Bartels, Caroline L. Relton, Craig E. Pennell, Leda Chatzi, Xavier Estivill, John W. Holloway, Dorret I. Boomsma, Grant W. Montgomery, Joanne M. Murabito, Tim D. Spector, Christine Power, Marjo-Ritta Ja ̈rvelin, Hans Bisgaard, Struan F.A. Grant, Thorkild I.A. Sørensen, Vincent W. Jaddoe, Bo Jacobsson, Mads Melbye, Mark I. McCarthy, Andrew T. Hattersley, M. Geoffrey Hayes, Timothy M. Frayling, Marie-France Hivert, Janine F. Felix, Elina Hyppo ̈nen, William L. , Jr Lowe, David M. Evans, Debbie A. Lawlor, Bjarke Feenstra, Rachel M. Freathy
URN:urn:nbn:de:kobv:517-opus4-423100
DOI:https://doi.org/10.25932/publishup-42310
ISSN:1866-8372
Parent Title (English):Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
Series (Serial Number):Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (628)
Document Type:Postprint
Language:English
Date of first Publication:2019/02/20
Year of Completion:2017
Publishing Institution:Universität Potsdam
Release Date:2019/02/20
Tag:alleles; biobanks; birth weight; duration of gestation; fetus; genetics; genome-wide association study; genotype; mothers; offspring; single nucleotide polymorphism
Issue:628
Pagenumber:15
Source:Human Molecular Genetics 27 (2018) 4, pp. 742–756 DOI 10.1093/hmg/ddx429
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
5 Naturwissenschaften und Mathematik / 59 Tiere (Zoologie) / 590 Tiere (Zoologie)
Peer Review:Referiert
Publication Way:Open Access
Licence (German):License LogoCreative Commons - Namensnennung, 4.0 International