Genetic Evidence for Causal Effects of Domain-Specific Physical Activity and Sedentary Behavior on Osteoporosis and...

Genetic factors contribute to physical activity (PA) and sedentary behavior (SB), two complex behavioral traits. They may be associated with musculoskeletal and inflammatory diseases. However, the relationships of domain-specific PA and SB traits with osteoporosis (OS), psoriatic arthritis (PsA), and rheumatoid arthritis (RA) remain unclear. A two-sample Mendelian randomization (MR) analysis assessed potential bidirectional associations between these behavioral traits and the three diseases.

GWAS summary statistics were used to examine five domain-specific PA traits, three SB traits, and OS, RA, and PsA. Primary causal estimates were obtained using the inverse-variance weighted (IVW) method. Complementary analyses used MR-Egger regression, the weighted median method, and the weighted mode method. Sensitivity analyses were performed using Cochran's Q test, the MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. Multiple testing was addressed using false discovery rate (FDR) correction.

In the forward MR analyses, genetically predicted liability to Light DIY was associated with lower odds of PsA after FDR correction (OR = 0.006, 95% CI = 0.0002-0.236, FDR-adjusted p = 0.018). Genetically predicted longer television viewing was linked to increased odds of PsA (OR = 2.205, 95% CI = 1.089-4.463, FDR-adjusted p = 0.028) and RA (OR = 1.006, 95% CI = 1.002-1.010, FDR-adjusted p = 0.004). Walking for pleasure showed a nominal inverse association with PsA, and computer use showed a nominal inverse association with RA. Neither association remained significant after FDR correction. No evidence of associations with the broad self-reported OS diagnosis was observed. Reverse MR analyses showed lower odds of Walking for pleasure (OR = 0.662, 95% CI = 0.484-0.906, FDR-adjusted p = 0.013) and Other exercises (OR = 0.651, 95% CI = 0.490-0.864, FDR-adjusted p = 0.006) for genetic liability to RA. RA liability was also associated with longer television viewing time (β = 0.708, 95% CI = 0.251-1.165, FDR-adjusted p = 0.006). No reverse associations were observed for PsA.

This bidirectional MR study identified several potential genetically predicted associations of domain-specific PA and SB traits with PsA and RA. The findings for television viewing and RA may suggest a potential bidirectional association. However, the results should be considered hypothesis-generating. These findings require independent replication and further validation before causal or clinical conclusions can be drawn.