Abstract Background Understanding how genetic factors interact with diet and lifestyle to influence obesity is critical as we move towards models of precision nutrition and medicine. Objectives To assess how genetic and lifestyle factors influence the variation in body composition and metabolic syndrome (Metsyn) risk factors. Methods A cross-sectional sample of age/sex/BMI-balanced 18–66 year old men and women (n = 211) from the USDA Nutritional Phenotyping Study were included in the analysis (NCT02367287). BMI polygenic risk scores (PRS) were calculated with the pgscalc pipeline. Associations with body composition and Metsyn traits were assessed by linear regression and ANCOVA. Explained variance was evaluated using sum of squares and partial R², with model constraint using Bayesian information criteria. Results The PRS independently explained 15. 6% of BMI variance and, after adjusting for age, sex, and genetic population structure, accounted for 11. 3% of BMI variance (p ANCOVA = 1. 1 × 10⁻⁷). Measures of diet quality, fitness, and resting metabolic rate (RMR) showed mixed independent associations with obesity traits. In best fit models, while the PRS was significant for DXA outcomes, waist circumference, and fasting TG, the explained variance was below 3% except in android-to-gynoid ratio (3. 3%), lean mass index (6. 6%), and waist circumference (10. 1%). The BMI PRS showed subtle associations with the metabolic/physiological consequences of obesity, only waist circumference and plasma glucose were associated with PRS. Blood pressure, triglycerides, and HDL levels were not associated with PRS for obesity. Conclusions The genetic factors influencing BMI appear to differ from those contributing to measures of adiposity and metabolic consequences of obesity. Genetic risk of high BMI was validated in this cohort, but sex, RMR, and fitness are the more refined determinants of adiposity and dysregulated metabolism in this healthy population. Future research should be sure to utilize genetic risk predictors specifically associated with maladaptive obesity traits rather than more broad associated phenotypes. Clinical trial registry NCT02367287
Arrington et al. (Fri,) studied this question.