Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Aims/hypothesis The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. Methods Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. Results Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β = −33 g [95% CI −55, −10], p = 0.004) and CDKAL1 rs7756992 (β = −22 g [95% CI −43, −1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (β = −20 g [95% CI −29, −11], p = 5 × 10⁻⁶). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (β = −16 g [95% CI −24, −8], p = 8 × 10⁻⁵). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (