| Title: | A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes |
| Journal: | Hepatology |
| Published: | 27 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39190705/ |
| DOI: | https://doi.org/10.1097/hep.0000000000001066 |
Publication 13077
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.</p>
APPROACH AND RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1 , TNKS , LYPLAL1 , and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD.</p>
CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.</p>
12 Keywords
- Fatty Liver
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genomics
- Hepatocytes
- Humans
- Lipid Metabolism
- Male
- Middle Aged
- Non-alcoholic Fatty Liver Disease
- United Kingdom
21 Authors
- Peter Saliba-Gustafsson
- Johanne M. Justesen
- Amanda Ranta
- Disha Sharma
- Ewa Bielczyk-Maczynska
- Jiehan Li
- Laeya A. Najmi
- Maider Apodaka
- Patricia Aspichueta
- Hanna M. Björck
- Per Eriksson
- Theresia M. Schurr
- Anders Franco-Cereceda
- Mike Gloudemans
- Endrina Mujica
- Marcel den Hoed
- Themistocles L. Assimes
- Thomas Quertermous
- Ivan Carcamo-Orive
- Chong Y. Park
- Joshua W. Knowles
1 Application
| Application ID | Title |
|---|---|
| 13721 | Causal associations of circulating biomarkers with cardiovascular disease |
Enabling scientific discoveries that improve human health