Additive interactions between genetic susceptibility and physical activity account for nearly one third of excess T2D risk

Regular physical activity is a well-established protective factor against type 2 diabetes (T2D), yet large variability exists in its metabolic benefits. Genetic factors could partially explain this variability, but studies examining gene-by-physical activity interactions in incident T2D are limited. Here, we used data from 10,627 participants from two population-based cohorts in the United States ( All of Us Research Program) and Denmark (Inter99) to investigate how genetic risk and physical activity jointly influence T2D risk. Genetic risk was characterized using a polygenic score for T2D. Physical activity was measured using wearable devices in All of Us and self-reported questionnaires in Inter99. In All of Us , T2D incidence rates per 1,000 person-years were 2.1 (95% CI: 0.3, 3.9) for individuals with high physical activity and low genetic risk and 18.3 (95% CI: 13.4, 23.3) for those with low physical activity and high genetic risk (multivariable-adjusted hazard ratio of 6.9 (95% CI: 3.3, 14.4)). The interaction between physical activity and genetic risk deviated from additivity, with a relative excess risk due to interaction of 0.40 (95% CI: 0.11, 0.69; p = 0.003), accounting for 27% (95% CI: 5, 50) of excess T2D risk. These results were replicated in Inter99, where 44% (95% CI: 22, 67) of excess T2D risk was attributed to the interaction. These findings provide consistent evidence of interactions between genetic risk and physical activity on T2D risk, indicating that increasing physical activity among those with high genetic risk may represent an effective strategy for precision T2D prevention.