Abstract
Frailty has become a major public health issue, but its association with Metabolic dysfunction-associated steatotic liver disease (MASLD) remains controversial. We conducted an observational study of frailty and MASLD using the frailty index (FI) and frailty phenotype (FP) in the UK Biobank. And the results were validated in the National Health and the All of Us Research Program (AoU) database. We explored the causal relationship and genetic correlation between frailty and MASLD. In the UK population, both pre-frail and frail individuals had increased risks of MASLD in the analyses of FI and FP. Notably, the odds ratios of FI to the occurrence of MASLD were even more significant in our study in the US population. The odds ratios were 2.75 ([95% CI 2.41-3.15]; P<0.001) for pre-frailty and 6.88 (95% CI 6.02-7.90; P<0.001) for frailty. There was significant causality (OR 2.00; [95% CI 1.40-2.86]; P<0.001) and positive genetic correlations (LDSC: rg =0.576, P<0.001; GNOVA: rg =0.777, P<0.001; ρ-HESS: rg =0.828) between FP and MASLD. Frailty greatly increases the risk of developing MASLD. There was a significant causal and positive genetic correlation between FP and MASLD.