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.

中文翻译：

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阐明新的因果代谢功能障碍相关脂肪肝疾病基因的功能基因组框架


背景和目标：代谢功能障碍相关的脂肪肝病（MASLD）是西方国家最普遍的慢性肝脏病理学，对公共卫生造成严重后果。由于来自肝脏脂肪的金标准磁共振定量的人类数据相对缺乏，鉴定 MASLD 致病基因的努力受到了阻碍。为了克服样本量不足的问题，已经使用了使用 MASLD 替代表型的全基因组关联研究，但迄今为止只确定了少量基因座。在这项研究中，我们将 MASLD 复合替代表型的 GWAS 与遗传共定位研究相结合，然后进行功能性体外筛选，以确定 MASLD 的真正致病基因。方法和结果：我们使用英国生物样本库来探索我们的新型MASLD评分和遗传共定位之间的关联，以优先考虑推定的致病基因进行体外验证。我们创建了一个功能基因组框架，以使用 CRISPRi 在体外研究 MASLD 基因。我们的数据确定 VKORC1 、 TNKS 、 LYPLAL1 和 GPAM 是肝细胞中脂质积累的调节因子，并表明 VKORC1 参与与 MASLD 发展相关的脂质储存。结论： 互补遗传学和基因组学方法可用于 MASLD 基因的鉴定。我们的数据支持 VKORC1 是真正的 MASLD 基因。我们已经建立了一个功能基因组框架，以大规模研究来自人类遗传关联研究的推定新型 MASLD 基因。