Sarcopenia Index Predicts the Risk of Liver Diseases: Genome-Wide Association Study and Polygenic Risk Score-Based Analyses in UK Biobank Cohort
Year: 2026
Type: article
Abstract: Background/Objectives: Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength, poses significant health risks. The sarcopenia index (SI) is an essential metric for quantifying sarcopenia, yet its genetic basis and implications on liver diseases remain poorly understood. Methods: We performed a genome-wide association study (GWAS) in 389,804 European individuals from the UK Biobank to identify genetic variants related to SI. Multiple post-GWAS analyses, including colocalization, transcriptome-wide association studies (TWAS), Mendelian randomization and LD score regression were analyzed. We used polygenic risk score (PRS) of SI followed by regression models and interaction analyses to evaluate the impact of SI PRS on the risk of alcoholic and non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, end-stage liver diseases (ESLD) and liver cancer. Results: Our analysis revealed 2476 genetic variants located near or within 406 genes associated with SI. Genetic colocalization and TWAS pinpointed 30 key variants that affect both SI and skeletal muscle gene expression. LD score regression and MR analyses both indicated inverse genetic correlations and links between SI and both NAFLD and liver fibrosis risk. Furthermore, SI PRS was associated with reduced risks of NAFLD (OR = 0.97 [95% CI 0.95–0.99], p = 0.028), liver fibrosis (OR = 0.93 [95% CI 0.90–0.96], p < 0.001), MASLD (OR = 0.98 [95% CI 0.97–0.99], p < 0.001), ESLD (OR = 0.97 [95% CI 0.94–0.99], p = 0.012), and liver cancer (OR = 0.98 [95% CI 0.96–1.00], p = 0.037), but not alcoholic liver disease (OR = 0.96 [95% CI 0.92–1.02], p = 0.120). SI PRS is also associated with the decline in fatty liver index and hepatic steatosis index in MASLD population. Restricted cubic spline analyses suggested potential linear relationships between SI PRS and liver diseases, including NAFLD, MASLD and liver fibrosis. However, gene–environment interaction analyses indicated that smoking, diabetes and metabolic status could further modify the liver disease risks in individuals with high SI PRSs. Conclusions: Our study discovered genetic variants for SI and revealed potential inverse associations of SI on the risk of NAFLD, MASLD, liver fibrosis, ESLD and liver cancer. These findings could facilitate risk stratification and support targeted therapeutic strategies for liver diseases.
Source: Biomedicines
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,137
OpenAlex ID: W7225613187