Genetic liability to sedentary behaviour and cardiovascular disease incidence in the FinnGen and HUNT cohorts

Objective Energy-saving sedentary behaviour may be an evolutionarily selected trait that is no longer advantageous. We investigated the associations between genetic liability to sedentary behaviour and the incidence of the most common cardiovascular disease (CVD). Methods We constructed and validated a genome-wide polygenic score for leisure screen time (PGS LST) as a measure of genetic liability to sedentary behaviour. We performed survival analyses between higher PGS LST and register-based CVDs using the FinnGen cohort (N=293 250–333 012). Replication and exploratory analyses were conducted in an independent Norwegian Trøndelag Health Study (HUNT) cohort (N=35 289). Results In FinnGen, each SD increase in PGS LST was associated with a higher risk of incident CVD (HR: 1.05 (95% CI 1.05 to 1.06)) (168 770 cases over 17 101 133 person-years). The magnitudes of association for the three most common CVDs were 1.09 ((95% CI 1.08 to 1.09), 1.06 ((95% CI 1.05 to 1.07) and 1.05 ((95% CI 1.04 to 1.06) for hypertensive disease, ischaemic heart disease and cerebrovascular disease, respectively. Those in the top decile of PGS LST had 21%, 35%, 26% and 19% higher risk of any CVD, hypertensive disease, ischaemic heart disease and cerebrovascular disease, respectively, than those in the bottom decile. Associations were replicated in HUNT and remained independent of covariates (socioeconomic status, body mass index and smoking) except for cerebrovascular disease. Besides direct effects, reduced physical activity served as a potential mediating pathway for the observed associations. Conclusions We found that genetic liability to sedentary behaviour is associated with incident CVD, although effect sizes with current PGS remained small. These findings suggest that genetic liability to sedentary behaviour is an under-recognised driver of common CVDs. Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. The used FTC subsample data are in the Biobank of the National Institute for Health and Welfare. Data are available for qualified researchers through a standardised application procedure (see the website for details). Access to individual-level genotypes and register data from FinnGen participants can be applied via the Fingenious portal () hosted by the Finnish Biobank Cooperative FinBB (). The register data also needs permission from FinData ([www.findata.fi][1]). Researchers affiliated with a Norwegian research institution can apply for HUNT data access from the HUNT Research Centre ([www.ntnu.edu/hunt][2]) if they have obtained project approval from the Regional Committee for Medical and Health Research Ethics (REC). Researchers not affiliated with a Norwegian research institution should collaborate with and apply through a Norwegian principal investigator. Information on the application and conditions for data access is available online ([www.ntnu.edu/hunt/data][3]). The HUNT Databank website provides a detailed overview of the available variables in HUNT ([www.ntnu.edu/hunt/databank][4]). Certain data from ancillary HUNT projects may be subject to a time-limited exclusivity provided to the researchers who have financed and conducted the data collection. Biological material is available for analyses, and information on procedures is found on the HUNT Biobank website ([www.ntnu.edu/hunt/hunt-biobank][5]). Data from the health registries are not kept by HUNT; instead, linkages between HUNT and registry data must be made for each research project and require that the principal investigator has obtained project-specific approval for such linkage from REC and each registry owner. [1]: https://findata.fi/en/ [2]: https://www.ntnu.edu/hunt [3]: https://www.ntnu.edu/hunt/data [4]: https://www.ntnu.edu/hunt/databank [5]: https://www.ntnu.edu/hunt/hunt-biobank