Objectives To 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.

Methods We 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 (V̇O2max) and high PGS CRF (group “inherited” CRF) to those having high CRF but low PGS CRF (group “gained” CRF), N=375 vs. 279, respectively.

Results Higher 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.

Conclusions PGS 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.

What is already known on this topic Cardiorespiratory 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 adds We 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 policy Genetic 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.

The authors have declared no competing interest.

The funders did not affect this study in any way. This work was funded by Research Council of Finland (grants 341750, 346509, and 361981), Juho Vainio Foundation; Päivikki and Sakari Sohlberg Foundation, all to ES. VL is funded by a University of Helsinki doctoral researcher position in the iCANDOC Doctoral Education Pilot in Precision Cancer Medicine. The FinnGen project is funded by Business Finland and 13 international pharmaceutical industry partners: AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene/Bristol-Myers Scibb, Genentech (a member of the Roche Group), GSK, Janssen, Maze Therapeutics, MSD/Merck, Novartis, Pfizer, and Sanofi. The HUNT study is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The genetic investigations of the HUNT study are a collaboration between researchers from the K.G. Jebsen Center for Genetic Epidemiology, NTNU, and University of Michigan Medical School, and the University of Michigan School of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa approved the study the FinnGen study protocol (HUS/990/2017). The Finnish Institute of Health and Welfare, the Digital and Population Data Service Agency, the Social Insurance Institution, and Statistics Finland approved the FinnGen study (THL/2031/6.02.00/2017). The Regional Committee for Medical and Health Research Ethics, the Trøndelag Health Study, the Norwegian Data Inspectorate, and the National Directorate of Health approved the HUNT study (REC; 2019/29771).

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