Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis.

Area of Science:

• Genomics
• Hepatology
• Systems Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) presents significant medical and socioeconomic challenges.
• Understanding the genetic underpinnings of MASLD is crucial for developing targeted therapies.

Purpose of the Study:

• To identify genetic variations influencing gene expression in MASLD using single-cell expression quantitative trait locus (sc-eQTL) analysis.
• To uncover cell-state-specific gene regulation and its contribution to MASLD heritability.

Main Methods:

• Performed sc-eQTL analysis on liver biopsies from patients with MASLD and healthy controls.
• Integrated transcription factor data to identify functional regulatory units (quartets).
• Analyzed genotype-specific regulation of gene expression in relation to MASLD risk.

Main Results:

• Identified over 3,500 sc-eQTLs across major liver cell types and cell-state-interacting eQTLs (ieQTLs).
• Demonstrated significant enrichment of ieQTLs for MASLD heritability (odds ratio 10.27).
• Discovered a functional quartet involving EFHD1, FOXO1, hepatocyte maladaptation, and MASLD risk.

Conclusions:

• sc-eQTL analysis is a powerful approach to dissecting genetic contributions to complex liver diseases like MASLD.
• Identified specific genetic regulatory mechanisms, such as FOXO1's role in EFHD1 regulation, contributing to MASLD.
• Findings pave the way for genotype-informed, personalized therapeutic strategies for MASLD.