A contextual genomic perspective on physical activity and its relationship to health, well-being and illness

Physical activity (PA) is one of the most fundamental of all traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program (MVP), we conducted genetic analyses of leisure, work, and home-time PA. For leisure, for individuals of European (EUR) ancestry, n=189,812 and SNP-based heritability ( h ² )=0.083±0.005; for African ancestry, n=27,044; h ² = 0.034±0.017; and for Latin-American ancestry, n=10,263; h ² = 0.083±0.036. EUR and cross-ancestry meta-analyses with UK Biobank identified 67 and 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit on pathologies and lifespan. Mendelian randomization analyses showed protective effects of leisure-time PA on cardiovascular and respiratory system diseases, metabolic traits, aging, and other traits, and there was protective role of leisure-time PA against COVID-19 hospitalization (β=-0.067±0.016; p -value=2.8×10 ^-5 ). These findings provide new insights into the biology of PA, showing the causal health benefits of leisure-time PA.