Genetically versus environmentally influenced obesity and risk of mortality and non-communicable diseases: A cohort study from the UK Biobank

Background Previous research indicate that obesity is less harmful in people with genetic predisposition to high body mass index (BMI), compared to obesity driven by other factors such as environment or lifestyle. Yet differences between genetically and environmentally influenced adiposity in relation to health outcomes remain unexplored, and have not examined adiposity measures beyond BMI. Therefore, we examined differences between genetically versus environmentally influenced adiposity, measured with BMI as well as waist-hip ratio (WHR), in relation to risk of mortality and key non-communicable diseases. Methods We followed 484,858 UK Biobank participants (aged 40–69 years at baseline) over on average 13 years. Baseline BMI and WHR categories were tested in interaction with polygenic scores (PGS) for respective trait, to distinguish between high adiposity influenced by genetic predisposition (obesity or high WHR and high PGS) versus by environmental factors (obesity or high WHR but low PGS). Risk of all-cause mortality, cardiovascular disease (CVD), cancers, chronic respiratory disease (CRD), and diabetes were modelled in Cox proportional hazard regression, adjusting for age, sex, ethnicity, and socioeconomic factors.. Results The PGS for BMI interacted with obesity, such that genetic predisposition to higher BMI attenuated obesity associations with CVD, diabetes, and CRD, but strengthened that with cancer. In contrast, the PGS for WHR had the opposite effect, and genetic predisposition to higher WHR instead amplified associations between high WHR and mortality, CVD, diabetes, and CRD. Conclusions Obesity was linked to lower risk for most outcomes in people with genetic predisposition to higher BMI, compared to those with genetic predisposition to a low BMI. This indicates that genetically influenced obesity may be less detrimental than obesity influenced by environmental factors sucha as lifestyle. In contrast, the opposite was seen when adiposity was measured as WHR, where the association between high WHR and most outcomes was stronger in people with genetic predisposition to higher WHR. This highlights that BMI and WHR capture distinct adiposity profiles with opposing genetic effects, and underscores the heterogeneity in obesity.