Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology

Objectives It has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus associates with CRF. Methods Genetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (n(total) = 3206). The body fat% GRS was created by summing the alleles of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO(2)max), per kg fat-free mass (VO(2)max(FFM)), or per kg fat mass (VO(2)max(FM)). All analyses were adjusted for age and sex, and when relevant, for body composition. Results We found a significant negative genetic correlation between VO(2)max and body fat% (rho G = -0.72 (SE +/- 0.13)). The body fat% GRS associated with decreased VO(2)max (beta = -0.15 mL/kg/min per allele, p = 0.0034, age and sex adjusted). The body fat%-increasing FTO allele was associated with a 0.42 mL/kg/min unit decrease in VO(2)max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat %. The fat% increasing GRS and FTO risk allele were associated with decreased VO(2)max(FM) but not with VO(2)max(FFM). Conclusions Our findings suggest a shared genetic etiology between whole body fat% and CRF.