TY - JOUR
T1 - A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes
AU - Saliba-Gustafsson, Peter
AU - Justesen, Johanne M.
AU - Ranta, Amanda
AU - Sharma, Disha
AU - Bielczyk-Maczynska, Ewa
AU - Li, Jiehan
AU - Najmi, Laeya A
AU - Apodaka, Maider
AU - Aspichueta, Patricia
AU - Björck, Hanna M
AU - Eriksson, Per
AU - Schurr, Theresia M.
AU - Franco-Cereceda, Anders
AU - Gloudemans, Mike
AU - Mujica, Endrina
AU - den Hoed, Marcel
AU - Assimes, Themistocles L
AU - Quertermous, Thomas
AU - Carcamo-Orive, Ivan
AU - Park, Chong Y
AU - Knowles, Joshua W
N1 - Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2024
Y1 - 2024
N2 - BACKGROUND 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 GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.APPROACH 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.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.
AB - BACKGROUND 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 GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.APPROACH 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.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.
U2 - 10.1097/HEP.0000000000001066
DO - 10.1097/HEP.0000000000001066
M3 - Journal article
C2 - 39190705
JO - Hepatology
JF - Hepatology
SN - 0270-9139
ER -