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

Area of Science:

• Genetics
• Epidemiology
• Cardiovascular Disease

Background:

• Aerobic fitness is crucial for overall health.
• Understanding genetic predispositions to fitness can reveal causal health links.
• Mendelian randomization (MR) is a powerful tool for inferring causality from genetic data.

Purpose of the Study:

• To investigate potentially causal associations between genetically predicted aerobic fitness and a wide range of health phenotypes.
• To utilize a two-stage phenome-wide Mendelian randomization (MR) approach for robust analysis.
• To identify specific health outcomes influenced by genetic predisposition to aerobic fitness.

Main Methods:

• Employed a two-stage MR study design using European-ancestry Genome-Wide Association Study (GWAS) summary statistics.
• Utilized genetically determined aerobic fitness as the exposure and screened 712 health phenotypes as outcomes.
• Applied the MR-Robust Adjusted Profile Score method and rigorous sensitivity analyses to ensure validity.

Main Results:

• Identified 34 statistically significant and validated associations between genetically predicted aerobic fitness and various health phenotypes.
• Higher genetically predicted aerobic fitness showed associations with favorable cardiometabolic traits, reduced inflammation, improved musculoskeletal and hepatic markers, and higher educational attainment.
• Adverse associations were observed for atrial fibrillation, valvular heart disease, and systolic blood pressure.

Conclusions:

• Genetically determined aerobic fitness is associated with a wide array of beneficial health outcomes across multiple physiological systems.
• The findings highlight the significant impact of genetic predisposition to aerobic fitness on diverse health phenotypes.
• While largely beneficial, potential cardiovascular risks warrant further investigation.