Discrepancy Between Genetically Predicted and Observed BMI Predicts Incident Type 2 Diabetes

Objective: Obesity is a key predictor of type 2 diabetes mellitus (T2D). However, metabolic complications are not solely due to increased body mass index (BMI). We hypothesized that differences between genetically-predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D. Research Design and Methods: From the UK Biobank cohort, we selected participants of European ancestry without T2D (n=332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional-hazards model. Independent data from the KoGES cohort from South Korea (n=7,430) were used for replication. Results: Participants from the UK Biobank were divided into train (n=268,041) and test set (n=115,119) to establish genetically-predicted BMI. In the test set, the genetically-predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 (3.1%) T2D cases during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically-predicted), had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: adjusted hazard ratio of 1st quintile (vs.5th quintile)=1.61 (1.26-2.05, P<0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity. Conclusions: Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.