Cardiorespiratory fitness, body composition, diabetes, and longevity: a two-sample Mendelian randomization study

Abstract Context Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality. Objective We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity. Methods Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional 2-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N ≈ 70 000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). Results Genetically predicted higher (per 1 SD increase) body fat percentage was associated with lower VO2max (β = −0.36; 95% CI: −0.40, −0.32, P = 6 × 10–77). Meanwhile, genetically predicted higher appendicular lean mass (β = 0.10; 95% CI: 0.08 to 0.13), physical activity (β = 0.29; 95% CI: 0.07 to 0.52), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (all P < .01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations. Conclusion Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.