Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.

Hao Dong; Yufeng Li; Qiang Ding; Miaoxin Zhang; Shuaipeng Gu; Mei Liu

doi:10.1002/gepi.70055

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Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.

Hao Dong·Yufeng Li·Qiang Ding·Miaoxin Zhang·Shuaipeng Gu·Mei Liu

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Abstract

Although individual traits related to metabolic dysfunction-associated steatotic liver disease (MASLD) have been investigated through large-scale genome-wide association studies (GWASs), the shared genetic susceptibility across these traits remains unclear. We therefore conducted a multivariate GWAS of key MASLD-related traits to elucidate their common genetic architecture. We applied genomic structural equation modeling to model a latent genetic factor (MASLD-F) underlying genetically correlated MASLD-related traits, leveraging their GWAS-derived genetic correlations. We then performed functional annotations, including fine-mapping, transcriptome-wide association study, and cell- and tissue-type-specific enrichment analyses, and conducted Mendelian randomization analyses to identify modifiable risk factors. Our multivariate MASLD-F GWAS identified 50 independent variants across 48 genomic loci. Transcriptomic imputation identified several MASLD-F-associated genes, including ARNTL, NPC1, BTBD10, VDAC2, TSKU, SFMBT1, and ABHD17C. We observed significant enrichment of MASLD-F-related genetic signals predominantly in brain tissues, pancreatic islets, and the adrenal gland. Additionally, six modifiable risk factors and four modifiable protective factors for MASLD-F were identified. These findings reveal a complex shared genetic architecture underlying MASLD components, thereby expanding our understanding of disease pathogenesis and providing novel insights for precision medicine and public health interventions.

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Humans Genome-Wide Association Study Fatty Liver Genetic Predisposition to Disease Polymorphism, Single Nucleotide Models, Genetic Risk Factors Non-alcoholic Fatty Liver Disease Phenotype genomic structural equation modeling metabolic dysfunction–associated steatotic liver disease metabolic syndrome shared genetic architecture Journal Article

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Hao Dong, Yufeng Li, Qiang Ding, Miaoxin Zhang, Shuaipeng Gu, Mei Liu. 2026. Revealing the Shared Genetic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Through Genomic Structural Equation Modeling.. https://doi.org/10.1002/gepi.70055

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Journal Article resource Fatty Liver subject Genetic Predisposition to Disease subject Genome-Wide Association Study subject Humans subject Journal Article subject Metabolic Syndrome subject Models, Genetic subject Phenotype subject Polymorphism, Single Nucleotide subject

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