Aerobic Fitness and Health-Related Phenotypes: A Two-Stage Phenome-Wide Mendelian Randomization Study

PURPOSE: We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. METHODS: Genetically determined aerobic fitness, as operationalized by Cai et al., served as the exposure instrument. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association studies (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for validation. Associations were estimated using the MR-Robust Adjusted Profile Score method, controlled for multiple testing (5% false discovery rate) and unaffected by violations of MR assumptions (directional concordance between discovery and validation; no evidence of horizontal pleiotropy across inverse-variance weighted, MR-Egger, weighted-median, and weighted-mode methods; negative control analysis on hair color). RESULTS: We identified 108 discovery associations, of which 34 remained valid and statistically significant after validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure. CONCLUSIONS: Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.