Deciphering the heterogeneity of early-onset type 2 diabetes using epidemiological and genetic approaches (360G-Wellcome-223024_Z_21_Z)

Background: Early-onset type 2 diabetes (diagnosed <40-years), is a severe presentation with excess risk of complications, cardiovascular events and early death, compared to later-onset disease. UK south Asian populations have an unexplained higher prevalence of this diagnosis. Studies of later-onset type 2 diabetes reveal heterogeneity in phenotype associating with complication risk, raising the possibility that targeting this variation with specific treatments could improve outcomes. These methods have not been extended to early-onset type 2 diabetes. Goal: I will decipher heterogeneity of early-onset type 2 diabetes in white and south Asian individuals using epidemiological and genetic approaches. Proposal: \- Determine whether early- onset type 2 diabetes is enriched for sub-phenotypes contributing to higher risk, using analysis of large datasets to examine ethnic differences in presentation and progression by age-at-diagnosis with application of supervised and unsupervised statistical methods. \- Determine if the higher risk of early-onset type 2 diabetes in south Asian individuals is driven by excess polygenic risk, by undertaking a cohort study with application of trans-ancestry polygenic scores compared to controls. Summary: This broad population-level study together with deep genotyping and phenotyping of affected individuals has the potential to produce new insights leading to better surveillance, earlier therapies, and fewer complications.