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Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

By 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, Early Growth Genetics (EGG) Consortium, 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, 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 Järvelin, Hans Bisgaard, Struan F.A. Grant, Thorkild IA 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 Hyppönen, William L Lowe, David M Evans, Debbie A Lawlor, Bjarke Feenstra, Rachel M. Freathy

Posted 11 Dec 2015
bioRxiv DOI: 10.1101/034207 (published DOI: 10.1093/hmg/ddx429)

Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about how maternal genetic variation influences fetal growth. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed GWAS 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 and CYP3A7) showed evidence of association with offspring birth weight at P<5x10-8. The SEM analyses showed 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 effects of maternal glucose, cytochrome P450 activity and gestational duration, and potential effects of maternal blood pressure and immune function on fetal growth. Further characterization of these associations, for example 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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