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

Area of Science:

• Genetics and Human Health
• Metabolic Disease Research
• Epidemiology

Background:

• Obesity is a primary risk factor for type 2 diabetes (T2D).
• Metabolic complications are not solely explained by elevated Body Mass Index (BMI).
• Individual differences in BMI relative to genetic predisposition may influence metabolic health.

Purpose of the Study:

• To investigate if the difference between genetically predicted BMI and observed BMI (BMI-diff) can predict incident type 2 diabetes (T2D).
• To explore the association between BMI-diff and T2D risk, accounting for observed BMI.
• To validate findings in an independent cohort.

Main Methods:

• Utilized UK Biobank (n=332,154) and Korean Genome and Epidemiology Study (KoGES, n=7,430) cohorts.
• Calculated polygenic risk score for BMI using PRS-CS.
• Assessed 10-year T2D risk using multivariable Cox proportional hazards models based on BMI-diff quintiles.

Main Results:

• In the UK Biobank test set, genetically predicted BMI explained 7.1% of BMI variance.
• Higher BMI-diff quintiles were significantly associated with increased T2D risk (HR 1.61 for 1st vs. 5th quintile, P < 0.001).
• Findings were replicated in the KoGES cohort and associated with impaired insulin sensitivity.

Conclusions:

• Elevated BMI beyond genetic prediction is linked to a higher risk of type 2 diabetes.
• BMI-diff offers a potential metric for refining T2D risk assessment.
• Genetic thresholds for BMI may aid in personalized T2D risk stratification.