Abstract
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.