Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

Mark McCarthy and colleagues report a genome-wide association study of birth weight. They identified two loci, in ADCY5 and near CCNL1 , that are associated with birth weight and explain 0.3% and 0.1% of the variance in birth weight, respectively. To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies ( n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies ( n = 27,591). rs900400 near LEKR1 and CCNL1 ( P = 2 × 10 −35 ) and rs9883204 in ADCY5 ( P = 7 × 10 −15 ) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes 1 , providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes 2 , 3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight–lowering alleles were, on average, 113 g (95% CI 89–137 g) lighter at birth than the 24% with zero or one alleles ( P trend = 7 × 10 −30 ). The impact on birth weight is similar to that of a mother smoking 4–5 cigarettes per day in the third trimester of pregnancy 4 .