Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability.
Objective
We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI).
Design
First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus.
Results
Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci – UBXN2B/CYP7A1 and GIPR – are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae.
Conclusion
A genome-wide SNPxBMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR.
Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability.
Objective
We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI).
Design
First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus.
Results
Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci – UBXN2B/CYP7A1 and GIPR – are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae.
Conclusion
A genome-wide SNPxBMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR.
Date Issued
2025-10-01
Date Acceptance
2025-05-29
Citation
Clinical and Molecular Hepatology, 2025, 31 (4), pp.1252-1268
ISSN
2287-2728
Publisher
Korean Association for the Study of the Liver
Start Page
1252
End Page
1268
Journal / Book Title
Clinical and Molecular Hepatology
Volume
31
Issue
4
License URL
Identifier
10.3350/cmh.2025.0159
Publication Status
Accepted
Date Publish Online
2025-06-02