How do lifestyle factors modify the association between genetic predisposition and obesity-related phenotypes? A 4-way decomposition analysis using UK Biobank

Obesity and central obesity are multifactorial conditions with genetic and non-genetic (lifestyle and environmental) contributions. There is incomplete understanding of whether lifestyle modifies the translation from respective genetic risks into phenotypic obesity and central obesity, and to what extent genetic predisposition to obesity and central obesity is mediated via lifestyle factors.

This is a cross-sectional study of 201,466 (out of approximately 502,000) European participants from UK Biobank and tested for interactions and mediation role of lifestyle factors (diet quality; physical activity levels; total energy intake; sleep duration, and smoking and alcohol intake) between genetic risk for obesity and central obesity. BMI-PRS and WHR-PRS are exposures and obesity and central obesity are outcomes.

Overall, 42.8% of the association between genetic predisposition to obesity and phenotypic obesity was explained by lifestyle: 0.9% by mediation and 41.9% by effect modification. A significant difference between men and women was found in central obesity; the figures were 42.1% (association explained by lifestyle), 1.4% (by mediation), and 40.7% (by modification) in women and 69.6% (association explained by lifestyle), 3.0% (by mediation), and 66.6% (by modification) in men.

A substantial proportion of the association between genetic predisposition to obesity/central obesity and phenotypic obesity/central obesity was explained by lifestyles. Future studies with repeated measures of obesity and lifestyle would be needed to clarify causation.