The interaction of polygenic and monogenic diabetes to unravel new biology and diabetes subtypes (360G-Wellcome-219606_Z_19_Z)

We are now in the genomics era where clinical and pre-emptive genetic testing is common. This has raised new problems in monogenic disorders such as Maturity-Onset Diabetes of the Young (MODY), a rare genetic form of diabetes: 1) identification of wide variation in the clinical features of people with MODY mutations, including non-diabetic individuals. 2) identification of people who are ‘MODY-like’ (slim, young and not on insulin) but without a MODY mutation and therefore without a known cause for their diabetes. During my fellowship, I will address these new problems using our unique cohort of MODY/MODY-like diabetes and clinical and genetic data on 500,000 people from UK Biobank. I hypothesise that polygenic risk of diabetes-related traits will explain variation in the MODY phenotype and characterise new subtype(s) of diabetes which presents as classic MODY, but is due to extreme polygenic risk of diabetes-related traits (polygenic-phenocopies). The outcomes of this research will be to provide accurate prediction of which people with MODY mutations will get diabetes and when, and define and characterise a new type of diabetes. This work will have important implications for individuals with MODY, for the wider diabetes community and will provide framework for other genetic disorders.