Stratification of Type 2 Diabetes Mellitus by Age of Diagnosis in the UK Biobank Reveals Subgroup-Specific Genetic Associations and Causal Risk Profiles

The pathogenesis of type 2 diabetes mellitus (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis, to gain insight in the genetics and causal risk factors of T2D across different age groups. We performed genome-wide association studies (GWAS) on T2D and T2D subgroups based on age of diagnosis (<50 years, 50-60, 60-70, and >70 years; total of 24,986 cases). As controls, we used participants who were at least 70 years of age at the end of follow-up without developing T2D (N = 187,130). GWAS identified 208 independent lead SNPs mapping to 69 loci associated with T2D (p<1.0e-8). Among others, SNPs mapped to CDKN2B-AS1 and multiple independent SNPs mapped to TCF7L2 were more strongly associated to cases diagnosed after age 70 years than to cases diagnosed before age 50 years. Based on the different case groups, we performed two-sample Mendelian Randomization. Most notably, we observed that of the investigated risk factors the association between body mass index and T2D attenuated with increasing age of diagnosis. Collectively, stratification of T2D based on age of diagnosis reveals subgroup-specific genetics and causal determinants, supporting the hypothesis that the pathogenesis of T2D changes with increasing age.