Deviation From Genetically Predicted BMI and All-Cause Mortality: A Cohort Study in the UK Biobank.

Objective: The relation between genetically predicted BMI (gBMI) and actual BMI may have health effects. This study examines the relationship between deviations from gBMI and all-cause mortality in 208,146 UK Biobank participants.

Methods: We derived gBMI from polygenic risk scores, with deviations calculated as the difference between observed and predicted BMI. Cox proportional hazards models are adjusted for confounders and current BMI.

Results: Downward deviations (> 2 SD below gBMI) were associated with significantly increased mortality (HR: 1.25, 95% CI: 1.01-1.55), whereas upward deviations (> 2 SD above) showed no significant effect (HR: 1.10, 95% CI: 0.93-1.29). The mortality exhibited the known nonlinear J-shaped association with observed BMI, here lowest at BMI ~22 kg/m², but this nadir varied by genetic predisposition; thus, for individuals with high gBMI, lowest mortality occurred at higher observed BMI (24-26 kg/m²), while those with low or medium gBMI showed sharper increases in mortality at higher BMI.

Conclusions: These findings highlight the possible importance of aligning current BMI to genetic predisposition, and future research should examine BMI deviations and their long-term health effects. This perspective may inform personalized obesity management strategies to optimize health outcomes.