Type 2 Diabetes TCF7L2 Risk Genotypes Alter Birth Weight: A Study of 24,053 Individuals

The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7–29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15–45 g) increase in offspring birth weight (P=2.8×10−5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9–48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ∼0.15 standard deviation; P=1×10−4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the −30G→A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62–172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2×10−7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes–susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.