Maternal genome-wide association study identifies a fasting glucose variant associated with offspring birth weight

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 x 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.