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, Pa l.R. Njølstad, Ellen A. Nohr, Christoph Reichetzeder, Susan M. Ring, Katherine S. Ruth, Caroline L. Relton, Thorkild I.A. Sørensen, David M. Evans, Debbie A. Lawlor, Rachel M. Freathy*, Early Growth Genetics (EGG) Consortium

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

52 Citations (Scopus)
214 Downloads (Pure)

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.
Original languageEnglish
Article numberddx429
Pages (from-to)742-756
Number of pages15
JournalHuman Molecular Genetics
Volume27
Issue number4
Early online date3 Jan 2018
DOIs
Publication statusPublished - 15 Feb 2018

Keywords

  • alleles
  • birth weight
  • fetus
  • genotype
  • mothers
  • single nucleotide polymorphism
  • genetics
  • duration of gestation
  • genome-wide association study
  • offspring
  • biobanks

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Projects

    MRC UoB UNITE Unit - programme 4

    Davey Smith, G. & Evans, D.

    1/06/131/04/18

    Project: Research

    MRC UoB UNITE Unit - Programme 5

    Lawlor, D. A. & Lawlor, D. A.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 2

    Relton, C. L. & Relton, C. L.

    1/06/1331/03/18

    Project: Research

    Cite this

    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-Møller, E., Huikari, V., Metrustry, S., Lunetta, K. L., Painter, J. N., Hottenga, J. J., Allard, C., Barton, S. J., ... 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. [ddx429]. https://doi.org/10.1093/hmg/ddx429