Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics
Authors: 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 ,   Early Growth Genetics (EGG) Consortium, 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 , 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 , Järvelin 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. , Hyppönen Elina , Lowe William L. , Evans David M , Lawlor Debbie A. , Feenstra Bjarke , Freathy Rachel M. 
Published: December 2015

AbstractGenome-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, ACTL9andCYP3A7) showed evidence of association with offspring birth weight atP<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, GCKandTCF7L2) 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.