Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its medical and socioeconomic impacts, driven by diverse genetic and environmental factors. Here, to address the urgent need for individually tailored therapies, we show results from single-cell expression quantitative trait locus (sc-eQTL) analysis on liver biopsies from 25 patients with MASLD and 23 controls. This approach identified over 3,500 sc-eQTLs across major liver cell types and cell-state-interacting eQTLs (ieQTLs) with significant enrichment for disease heritability (for MASLD trait, ieQTL enrichment odds ratio 10.27). We integrated transcription factors as upstream regulators of ieQTLs, revealing 601 functional units ('quartets') composed of transcription factors, cell states, SNP components of ieQTL (ieSNPs) and Gene component of ieQTL (ieGenes). From these results, we pinpoint the loss of an eQTL in EFHD1 during hepatocyte maladaptation associated with genotype-specific regulation by FOXO1, further contributing to the risk of MASLD. Our approach underscores the role of eQTL analysis in capturing crucial genetic variations that influence gene expression and clinical outcomes in complex diseases.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.