Genetic liability to sedentary behavior increases the risk of cardiovascular disease incidence: Evidence from the FinnGen cohort with 293,250 individuals

BackgroundIt 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. MethodsLeisure 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 (Trondelag 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. ResultsIn the FTC, each standard deviation increase in PGS LST was associated with greater self-reported LST (hours/day) ({beta} = 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. ConclusionsA 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. Clinical perspectiveWhat is new? O_LIIt is not known whether a genetic liability to sedentary behavior is a mutual underlying factor for both sedentary behavior and incident cardiovascular disease at the population level. C_LIO_LIWe observed that a higher polygenic score for leisure screen time was associated with more self-reported leisure screen time and a higher risk of common cardiovascular diseases. C_LI What are the clinical implications? O_LIThis study provides novel insights into the relationship between genetic predisposition to sedentary behavior and the development of cardiovascular diseases, shedding light on a previously underexplored aspect of disease etiology. C_LIO_LIThese results may motivate health professionals to encourage sedentary persons to undertake at least some physical activity. C_LI