Abstract
BACKGROUND: Interplay between lifestyle risk scores (LRSs) and genetic risk scores (GRSs) on obesity and related chronic diseases are underinvestigated and necessary for understanding obesity causes and developing prevention strategies. OBJECTIVES: This study aimed to investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer. METHODS: In this cohort study of 444,957 UK Biobank participants [age: 56.5 ± 8.1 y; BMI (in kg/m(2)): 27.4 ± 4.7], LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor had 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n = 106,301) was defined as baseline BMI ≥30. Incident diabetes (n = 16,311), CVD (n = 18,076), and obesity-related cancer (n = 17,325) were ascertained through linkage to registries over a median of 12-y follow-up. RESULTS: The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P < 0.021). Comparing the top with bottom LRS quintile, prevalence differences (95% CIs) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per SD increase in LRS were greater in the top than that in the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-fold, 3.81-fold, 1.56-fold, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, than those from bottom quintiles of both scores. CONCLUSIONS: Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.