Muscle Mass as a Causal Factor in MASLD: Insights from a Genome-Wide Association Study and Bidirectional Mendelian Randomization Using Data from the Korean Genome and Epidemiology Study

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern due to its increasing prevalence and associated risk of severe complications. Although body composition, such as fat and muscle mass, has been linked to MASLD, evidence on the causality of this relationship remains limited. This study investigated the potential causal relationships between body composition and MASLD using epidemiological methods. Methods: Data from the Korean Genome and Epidemiology Study were analyzed. MASLD patients were defined according to the hepatic steatosis index (≥36) and the fibrosis 4 index (≥1.30); individuals with both of these values in normal ranges were considered nonpatients. Body composition was assessed according to fat mass, muscle mass, and the waist-to-hip ratio using bioelectrical impedance analysis. Genome-wide association studies were conducted to identify single-nucleotide polymorphisms (SNPs) linked to body composition and MASLD. These SNPs were then used as instrumental variables in bidirectional Mendelian randomization (MR) analysis to determine causality. Results: A total of 258 MASLD patients and 3,498 nonpatients were included. The MR analysis showed that individuals in the lowest tertile of muscle mass had a higher prevalence of MASLD than those in the 2nd and 3rd tertiles (odds ratio, 1.57; 95% confidence interval, 1.09 to 2.27; p=0.02), whereas the reverse causal effect of MASLD on muscle mass was not significant. No significant causal relationships were identified between fat mass or the waist-to-hip ratio and MASLD, although these analyses were limited by several statistical constraints, such as relatively low F-statistics and potential heterogeneity. Conclusions: The findings demonstrate that muscle mass exerts a causal effect on the prevalence of MASLD, suggesting that modulating muscle mass could serve as an effective strategy for managing the disease.