TY - JOUR T1 - Maternal genome-wide association study identifies a fasting glucose variant associated with offspring birth weight JF - bioRxiv DO - 10.1101/034207 SP - 034207 AU - Bjarke Feenstra AU - Alana Cavadino AU - Jessica Tyrrell AU - George McMahon AU - Michael Nodzenski AU - Momoko Horikoshi AU - Frank Geller AU - Ronny Myhre AU - Rebecca C. Richmond AU - Lavinia Paternoster AU - Jonathan P. Bradfield AU - Eskil Kreiner-Møller AU - Ville Huikari AU - Sarah Metrustry AU - Kathryn L. Lunetta AU - Jodie N. Painter AU - Jouke-Jan Hottenga AU - Catherine Allard AU - Sheila J. Barton AU - Ana Espinosa AU - Julie A. Marsh AU - Catherine Potter AU - Wei Ang AU - Diane J. Berry AU - Luigi Bouchard AU - Shikta Das AU - Hakon Hakonarson AU - Jani Heikkinen AU - Berthold Hocher AU - Albert Hofman AU - Hazel M. Inskip AU - Manolis Kogevinas AU - Penelope A. Lind AU - Letizia Marullo AU - Sarah E. Medland AU - Jeffrey C. Murray AU - Ellen A. Nohr AU - Christoph Reichetzeder AU - Susan M. Ring AU - Loreto Santa-Marina AU - Denise M. Scholtens AU - Sylvain Sebert AU - Verena Sengpiel AU - Meike Bartels AU - Caroline L. Relton AU - Craig E. Pennell AU - Leda Chatzi AU - Xavier Estivill AU - John W. Holloway AU - Dorret I. Boomsma AU - Grant W. Montgomery AU - Joanne M. Murabito AU - Tim D. Spector AU - Christine Power AU - Marjo-Ritta Järvelin AU - Hans Bisgaard AU - Struan F.A. Grant AU - Thorkild I.A. Sørensen AU - Vincent W. Jaddoe AU - Bo Jacobsson AU - Mads Melbye AU - Mark I. McCarthy AU - Andrew T. Hattersley AU - M. Geoffrey Hayes AU - David M. Evans AU - Marie-France Hivert AU - Janine F. Felix AU - Elina Hyppönen AU - William L. Lowe, Jr. AU - Debbie A. Lawlor AU - Timothy M. Frayling AU - Rachel M. Freathy AU - for the Early Growth Genetics (EGG) Consortium Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/12/11/034207.abstract N2 - Several common fetal genetic variants have been associated with birth weight, but little is known about how maternal genetic variation influences fetal growth through the intra-uterine environment. To identify maternal genetic variants associated with birth weight, we performed a meta-analysis of 11 genome-wide association studies (GWAS; n = 19,626 women of European descent). We selected 18 single nucleotide polymorphisms (SNPs) for replication analysis in up to 13 further studies (n = 18,319 women of European descent). One SNP reached genome-wide significance (rs10830963, P = 2.0 × 10−11) in a combined analysis of discovery and replication results. Rs10830963 is intronic in MTNR1B and is known from previous GWAS to be associated with fasting glucose levels, type 2 diabetes and gestational diabetes. Each copy of rs10830963-G (the allele associated with higher fasting glucose) corresponded to a 31g [95%CI: 22, 41g] higher offspring birth weight. The association between maternal rs10830963 and birth weight was unaltered by adjustment for any potentially confounding effects of fetal genotype in 8716 maternal-fetal pairs. Although no other SNPs reached genome-wide significance, there was an excess of low P-values among SNPs known to be associated with fasting glucose levels. Our study demonstrates that maternal genetic variation at MTNR1B influences offspring birth weight and supports a broader role of genetic variation affecting maternal glucose levels in fetal growth. Our study also highlights that the effect sizes of associations between other maternal genetic variants and birth weight are unlikely to exceed 20g per allele, and therefore much larger sample sizes will be required to detect them. ER -