The pathogenesis of type 2 diabetes (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis to gain insight into 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, 50-60, 60-70, and >70 years) (total of 24,986 cases). As control subjects, participants were at least 70 years of age at the end of follow-up without developing T2D (N =187,130). GWAS identified 208 independent lead single nucleotide polymorphism (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 with cases diagnosed after age 70 years than with 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 BMI and T2D attenuated with increasing age of diagnosis. Collectively, our results indicate that stratification of T2D based on age of diag-nosis reveals subgroup-specific genetics and causal determinants, supporting the hypothesis that the pathogenesis of T2D changes with increasing age.
Pubmed ID: 33972266 RIS Download
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Software providing a set of functions to generate high-resolution Venn and Euler plots. Includes handling for several special cases, including two-case scaling, and extensive customization of plot shape and structure.
View all literature mentionsBiobank provides data collected at Assessment Center and via online questionnaires on participants aged 40-69 years recruited throughout United Kingdom and provides summary information to improve prevention, diagnosis and treatment of serious and life threatening illnesses.
View all literature mentionsSoftware R package for performing Mendelian randomization using genome wide association study summary data.
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