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<p>Genome-wide association studies have identified &gt;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 <i>SLC22A3</i> and key triglyceride metabolism regulators (<i>APOA5</i>, <i>ANGPTL3</i> and <i>LPL</i>), 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.</p>

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Integrative analyses elucidate transcriptional regulatory functions of risk alleles for metabolic liver disease

  • 期刊论文

  • 发表日期：

    2026年6月2日

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  • Biying Zhu,
  • Na He,
  • Yang Xiao,
  • Bin Chen,
  • Chen Li,
  • Ravi Mandla,
  • Yifan Liu,
  • Jiayu Zhang,
  • Xiao Chang,
  • Fulong Yu,
  • Marijana Vujkovic,
  • Julie A. Lynch,
  • Kyong-Mi Chang,
  • Bogdan Pasaniuc,
  • Daniel J. Rader,
  • Mitchell A. Lazar,
  • Wenxiang Hu

摘要

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.