Background It is unclear how the genetics of sedentary behavior are associated with incident cardiovascular disease (CVD). We investigated the associations between genetic liability to sedentary behavior, sedentariness, and four main CVD outcomes: any CVD, hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases. Methods Leisure screen time was used as a proxy for sedentary behavior. We developed a polygenic score for leisure screen time (PGS LST) based on over 890,000 genetic variants. We tested the validity of this score against self-reported LST in the older Finnish Twin Cohort (FTC, N=2,689, mean age of 60.5±3.7 years, 54.7% women) using linear regression. We examined the associations between PGS LST and register-based records of CVDs using survival models among FinnGen participants (N=293,250-333,012, 67.0±13.0 years at follow-up, 52.3% women). We replicated analyses in an independent cohort (Trøndelag Health Study [HUNT], N=35,289, 64.0±13.1 years, 51.6% women) and explored if the associations persist following adjustments for socioeconomic status, body mass index, and smoking or are mediated via reduced physical activity. Results In the FTC, each standard deviation increase in PGS LST was associated with greater self-reported LST (hours/day) (β = 0.09, 95% CI: 0.05-0.14). In FinnGen, each standard deviation increase in PGS LST was associated with a higher risk of incident CVD (hazard ratio: 1.05, [1.05-1.06]) (168,770 cases over 17,101,133 person-years).The magnitudes of association for three most common CVDs were 1.09 (1.08-1.09), 1.06 (1.05-1.07), and 1.05 (1.04-1.06) for hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases, respectively. Those in the top decile of PGS LST had 21%, 35%, 26%, and 19% higher risk of any CVD, hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases, respectively, than those in the bottom decile. Associations replicated in HUNT and remained independent of covariates except for cerebrovascular diseases. Besides direct effects, reduced physical activity served as a potential mediating pathway for the associations. Conclusions A higher genetic liability to sedentary behavior is associated with a greater risk of developing CVDs, although effect sizes with current PGS remain small. Our findings suggest that genetic liability to sedentary behavior is an underrecognized driver of common CVDs.

The authors have declared no competing interest.

The funders were not involved in planning, analyzing, or drafting the manuscript in any way. The study and FTC data collection were funded by the Research Council of Finland (grants 341750, 346509 and 361981 to ES, grants 265240, 263278, 100499, 205585, 118555, 141054, 264146, 308248, 312073, 336823, and 352792 to JK); the Juho Vainio Foundation to ES; the Paivikki and Sakari Sohlberg Foundation to ES; and the Sigrid Juselius Foundation, the Wellcome Trust Sanger Institute, the Broad Institute, and the European Network for Genetic and Genomic Epidemiology to JK. The FinnGen project is funded by Business Finland and thirteen 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), Trondelag 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 KG Jebsen Center for Genetic Epidemiology, NTNU, the University of Michigan Medical School, and the University of Michigan School of Public Health. The KG Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen, Faculty of Medicine and Health Sciences, NTNU, Norway.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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

Ethical approvals granted by ethical committees of University of Helsinki (113/E3/01 and 346/E0/05), Helsinki University Central Hospital (136/E3/01, 01/2011, 270/13/03/01/2008, 154/13/03/00/2011, HUS/1799/2017), the Finnish Institute for Health and Welfare (THL/4743/6.02.04/2021), Fimea (the National Supervisory Authority for Welfare and Health), Regional Committee for Medical and Health Research Ethics (REC; 2019/29771), the Trøndelag Health Study, the Norwegian Data Inspectorate, and the National Directorate of Health.

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The utilized FTC subsample data are in the Biobank of the National Institute for Health and Welfare. Data are available for qualified researchers through a standardized application procedure (see the website https://thl.fi/en/web/thl-biobank/for-researchers for details). Access to individual-level genotypes and register data from FinnGen participants can be applied via the Fingenious portal (https://site.fingenious.fi/en/) hosted by the Finnish Biobank Cooperative FinBB (https://finbb.fi/en/). The register data also needs permission from FinData (www.findata.fi). Researchers affiliated with a Norwegian research institution can apply for HUNT data access from the HUNT Research Centre (www.ntnu.edu/hunt) 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). The HUNT Databank website provides a detailed overview of the available variables in HUNT (www.ntnu.edu/hunt/databank). 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). 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.