Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease

生物 非酒精性脂肪肝 全基因组关联研究 遗传学 脂肪肝 内科学 基因 单核苷酸多态性 基因型 疾病 医学
作者
Yanhua Chen,Xiaomeng Du,Annapurna Kuppa,Mary F. Feitosa,Lawrence F. Bielak,Jeffrey R. O’Connell,Solomon K. Musani,Xiuqing Guo,Bratati Kahali,Vincent Chen,Albert V. Smith,Kathleen A. Ryan,Gudny Eirksdottir,Matthew Allison,Donald W. Bowden,Matthew J. Budoff,J. Jeffrey Carr,Yii‐Der Ida Chen,Kent D. Taylor,Antonino Oliveri,Adolfo Correa,Breland Crudup,Sharon L. R. Kardia,Thomas H. Mosley,Jill M. Norris,James G. Terry,Jerome I. Rotter,Lynne E. Wagenknecht,Brian Halligan,Kendra A. Young,John E. Hokanson,George R. Washko,Vilmundur Guðnason,Michael A. Province,Patricia A. Peyser,Nicholette D. Palmer,Elizabeth K. Speliotes
出处
期刊:Nature Genetics [Springer Nature]
卷期号:55 (10): 1640-1650 被引量:54
标识
DOI:10.1038/s41588-023-01497-6
摘要

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics. Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.
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