Associations of lifestyle and genetic risks with obesity and related chronic diseases in the UK Biobank: a prospective cohort study

Interplay between lifestyle (LRS) and genetic risk scores (GRS) on obesity and related chronic diseases are under-investigated and necessary for understanding obesity causes and developing prevention strategies. 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. In this cohort study of 444,957 UK Biobank participants (age: 56.5 ± 8.1 years, body mass index [BMI]: 27.4 ± 4.7 kg/m2), LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor has 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 kg/m2. 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-year follow-up. 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 versus bottom LRS quintile, prevalence differences (95% confidence intervals) 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 standard deviation increase in LRS were greater in the top compared to the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-, 3.81-, 1.56-, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, compared with those from bottom quintiles of both scores. 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.