Genetic Contribution of Cardiorespiratory Fitness in Morbidity and Mortality: A Prospective FinnGen and HUNT study

ObjectivesTo quantify the contribution of cardiorespiratory fitness (CRF) genetics in common non-communicable disease (NCD) and mortality risk and to assess whether health discrepancies exist between "inherited" and "gained" CRF. MethodsWe used a validated SBayesR-based genome-wide polygenic score, leveraging information from 905,707 single-nucleotide polymorphisms, to measure CRF genetics (PGS CRF). Associations with register-based incident cardiovascular disease, cancer, pulmonary disease, type 2 diabetes (T2D), and all-cause mortality were analysed using Cox proportional hazards models in the FinnGen cohort (N=262,137; 53.5-y at baseline, 52.0% women) and replicated in the HUNT3 cohort (N=26,115; 59.0-y, 52.4% women). In HUNT3, we also compared the health characteristics and disease risk of individuals having age- and sex-specific high CRF ([V]O2max) and high PGS CRF (group "inherited" CRF) to those having high CRF but low PGS CRF (group "gained" CRF), N=375 vs. 279, respectively. ResultsHigher PGS CRF was associated with lower risk of lung cancer (hazard ratio [HR] 0.95, 95% confidence interval 0.93-0.98), chronic obstructive pulmonary disease (HR 0.98, 0.96-1.00), T2D (HR 0.98, 0.96-0.99), and all-cause mortality (HR 0.98, 0.98-0.99) in the most adjusted model per each standard deviation increase in PGS. In sensitivity analyses including never-smokers, the association between PGS CRF and T2D remained statistically significant. Replication analyses supported main observations. No differences in health outcomes were observed between individuals with "inherited" and "gained" CRF. ConclusionsPGS CRF requires further development, but the findings suggest genetic predisposition accounts for some, albeit a limited proportion, of the public health benefits observed with CRF. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSCardiorespiratory fitness (CRF) is a well-known correlate of health and longevity, with an expected strong genetic component. However, it is not known to what extent genetics explain the health benefits of CRF or if "inherited" CRF is more health-protective than CRF "gained" through exercise. What this study addsWe found that current polygenic metrics for CRF show modest protective associations against type 2 diabetes, but not against cardiovascular disease, cancers, pulmonary disease or all-cause mortality after controlling for potential covariates. We did not observe differential associations between "inherited" and "gained" CRF with health outcomes. How this study might affect research, practice or policyGenetic confounding is expected to play a limited role in the relationship between CRF and the risk of common NCDs and mortality. Therefore, promotion of CRF remains a viable public health strategy.