Physical activity, but not sedentary behavior, affects bone mineral density: Insights from a comprehensive...

The shared genetic architecture linking physical activity, sedentary behavior, and osteoporosis risk remains unclear. We investigated the genetic basis, pleiotropic effects, and causal relationships between moderate-to-vigorous physical activity (MVPA), leisure screen time (LST), and heel estimated bone mineral density (eBMD). Leveraging summary statistics from genome-wide association studies of European individuals (MVPA: N = 606,820; LST: N = 526,725; eBMD: N = 426,824), we conducted a genome-wide cross-trait analysis. A significant global genetic correlation was observed for MVPA and eBMD ($r_g$ = 0.13, P = 7.97 × 10^-11), but not for LST and eBMD ($r_g$ = $-$ 0.02, P = 0.34). Two specific genomic regions showed evidence of local genetic correlation. Cross-trait meta-analysis identified 90 pleiotropic loci, of which 20 were novel. Transcriptome-wide association studies revealed 42 shared genes. Mendelian randomization suggested a causal relationship between genetically predicted MVPA and eBMD (beta = 0.07, 95%CIs = 0.01-0.14, P = 0.03), but not for LST (beta = 0.01, 95%CIs = $-$ 0.04-0.05, P = 0.81). Our findings demonstrate a shared genetic basis and pleiotropic effects between MVPA and eBMD, highlighting their intrinsic link and supporting MVPA's role in osteoporosis prevention.