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 Trondelag 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.