Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children

Abstract

Objective: To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.

Research design and methods: A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.

Results: Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021-0.031) for each unit increase in the score.

Conclusions: Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.

FIG. 1.

Effects of fasting glucose–associated variants in children, adolescents, and adults (in order of decreasing adult effect sizes).

FIG. 2.

Mean fasting glucose (95% CI) by categories of the genetic fasting glucose risk score in 822 boys and 960 girls of EYHS.