Figure 1.

Genetic and environmental influences combine and interact to cause type 1 diabetes. Their strength and relative contribution determine rate of progression through preclinical stages and, thus, the age at clinical onset of type 1 diabetes. The burden of type 1 diabetes–associated genes (as measured by type 1 diabetes GRS) is highest in young children who develop clinical type 1 diabetes. In particular, genes related to the immune function (e.g., IL2RA, THEMIS, etc.) are associated with very early-onset type 1 diabetes and characteristically aggressive histopathology. GLIS3 variants, which have been associated with very early-onset type 1 diabetes in the study by Inshaw et al. (7), is also involved in type 2 and monogenic diabetes. Studies in adult-onset type 1 diabetes have found a higher burden of type 2 diabetes genes. Twin studies support that environmental factors are less important at younger ages of onset. Interactions at various levels (gene-gene, gene-environment) have been described and could modify the relative importance of factors. T1D, type 1 diabetes; T2D, type 2 diabetes; y/o, years old.