Polygenic Background Contributes to GCK-MODY Clinical Presentation and Glycaemic Variability

Aims/HypothesisGCK-MODY (Glucokinase-Maturity Onset Diabetes of the Young) causes lifelong, mild hyperglycaemia with high penetrance. Variation in glycaemic phenotype among carriers remains unexplained. We hypothesised that polygenic background contributes to this variability. MethodsTo test whether polygenic background contributes to the GCK-MODY clinical phenotype, we analysed polygenic risk scores (PGS) for nine diabetes-related traits in 901 clinically referred individuals with GCK-MODY. We compared these to 7,645 non-diabetic controls and assessed associations between PGSs and glycaemic measures. Additionally, we evaluated 158 unselected GCK variant carriers from the UK Biobank to examine polygenic effects independent of clinical referral. ResultsWe observed independent polygenic enrichment for HbA1c (including both glycaemic and non- glycaemic components), fasting glucose, and type 2 diabetes in clinically referred GCK-MODY individuals (0.16-0.33 SD higher, all P < 0.003), but not for type 1 diabetes. In contrast, no such enrichment was seen in GCK pathogenic variant carriers from a clinically unselected population- based cohort. In both settings, HbA1c PGSs were associated with measured HbA1c levels in GCK carriers ({beta} = 0.91- 0.97, all P < 0.009), with effect sizes similar to those in non-carriers. GCK-MODY cases in the top HbA1c quintile had a 3-to-6-fold risk of exceeding the diabetes diagnostic HbA1c threshold ([&ge;] 48 mmol/mol) in clinically selected and clinically unselected cohort respectively. Conclusions/interpretationOur findings suggest that polygenic background and GCK variants interact to modify the glycaemic expression of GCK-MODY, influencing clinical diagnosis despite high penetrance. Our study highlights the importance of integrating both monogenic and polygenic factors to better understand phenotypic variability in monogenic diseases. Research in ContextO_ST_ABSWhat is already known about the subject?C_ST_ABSO_LIAlthough GCK-MODY shows high penetrance, individuals vary in their glycaemic phenotype, and the cause of this variability remains unclear. C_LIO_LIPolygenic background has previously been found to modify disease risk and phenotypic variability in other lower penetrant forms of MODY but its contribution to the clinical variability in GCK-MODY is largely unexplored C_LI What is the key question?O_LIDoes polygenic background for diabetes-related traits contribute to variation in the GCK- MODY phenotype? C_LI What are the new findings?O_LIWe identified that clinically referred GCK-MODY cases had an independent enrichment of HbA1c, fasting glucose, and type 2 diabetes polygenic background, potentially increasing the likelihood of clinical referral. C_LIO_LIHigher HbA1c polygenic risk in GCK-MODY was associated with elevated measured HbA1c levels and an increased probability of exceeding the diagnostic threshold for diabetes. C_LI How might this impact on clinical practice in the foreseeable future?O_LIPolygenic background shapes the clinical expression of GCK-MODY, supporting the integration of monogenic and polygenic information to explain variability in monogenic disease. C_LI