Medical College of Wisconsin
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Integrative analyses elucidate transcriptional regulatory functions of risk alleles for metabolic liver disease. Nat Genet 2026 Jun;58(6):1280-1294

Date

06/03/2026

Pubmed ID

42230773

DOI

10.1038/s41588-026-02617-8

Scopus ID

2-s2.0-105041076315 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Genome-wide association studies have identified >100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the mechanisms by which noncoding variants alter disease risk remain unclear. Here we map chromatin accessibility in human MASLD liver nuclei, revealing enrichment of risk variants within cell-type-specific regulatory elements bound by lineage-determining transcription factors. Using a massively parallel reporter assay, we identified hundreds of differential activity variants (DAVs) that act in a cell-type-dependent and stimulus-dependent manner and perturb transcriptional regulatory networks linked to liver pathology. Integration of liver expression quantitative trait loci, chromatin looping and single-cell CRISPR interference screening assigns target genes to these DAVs. Importantly, DAVs at numerous loci, including SLC22A3 and key triglyceride metabolism regulators (APOA5, ANGPTL3 and LPL), modulate gene expression, lipid metabolism and hepatic stellate cell activation. Moreover, these DAVs allow improved prediction of MASLD risk. These results define a regulatory framework linking noncoding genetic variation to MASLD pathogenesis.

Author List

Zhu B, He N, Xiao Y, Chen B, Li C, Mandla R, Liu Y, Zhang J, Chang X, Yu F, Vujkovic M, Lynch JA, Chang KM, VA Million Veteran Program, Pasaniuc B, Rader DJ, Lazar MA, Hu W

Author

Yang Xiao Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Chromatin
Fatty Liver
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Lipid Metabolism
Liver
Quantitative Trait Loci
Transcription, Genetic