A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes

Abstract

AbstractBackground & AimsNon-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD 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 NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD.Approach & ResultsWe used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes forin vitrovalidation. We created a functional genomic framework to study NAFLD genesin vitrousing CRISPRi. Our data identifyVKORC1, TNKS, LYPLAL1andGPAMas regulators of lipid accumulation in hepatocytes and suggest the involvement ofVKORC1in the lipid storage related to the development of NAFLD.ConclusionsComplementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supportsVKORC1as abona fideNAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.