Modifiable Lifestyle, Sedentary Behaviors and the Risk of Frailty: A Univariate and Multivariate Mendelian Randomization Study

Abstract This research conducted a two‐sample univariate and multivariate Mendelian Randomization (MR) analysis to explore the causal link between different types of leisure sedentary behavior (LSB) and frailty. Independent instrumental variables significantly associated with sedentary behaviors ( p < 5 × 10 −8 ) are obtained from a genome‐wide association study (GWAS) of 422,218 individuals, and Frailty Index (FI) are derived from the latest GWAS dataset of 175,226 individuals. MR analysis is conducted using inverse variance weighting, MR‐Egger, weighted median, simple mode, and weighted mode, supplemented by MRAPSS. Univariate MR revealed that sedentary behaviors such as watching television increased the risk of frailty (OR, 1.271; 95% CI: 1.202‐1.345; p = 6.952 × 10 −17 ), as sedentary driving behaviors are done (OR, 1.436; 95% CI: 1.026‐2.011; p = 0.035). Further validation through APSS, taking into account cryptic relatedness, stratification, and sample overlap, maintained the association between television viewing and increased frailty risk (OR, 1.394; 95% CI: 1.266‐1.534; p = 1.143 × 10 −11 ), while the association with driving dissipated. In multivariate inverse variance weighted (IVW) analysis, after adjusting for C‐reactive protein (CRP) levels, television Sedentary behavior (SB) inversely affected frailty (OR, 0.782; 95% CI: 0.724‐0.845; p = 4.820 × 10 −10 ). This study indicates that televisio SB significantly increases the risk of frailty, suggesting potential biological heterogeneity behind specific sedentary activities. This process may interact with inflammation, influencing the development of frailty.