학술논문
Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease
Document Type
Article
Author
Chen, Yanhua; Du, Xiaomeng; Kuppa, Annapurna; Feitosa, Mary F.; Bielak, Lawrence F.; O’Connell, Jeffrey R.; Musani, Solomon K.; Guo, Xiuqing; Kahali, Bratati; Chen, Vincent L.; Smith, Albert V.; Ryan, Kathleen A.; Eirksdottir, Gudny; Allison, Matthew A.; Bowden, Donald W.; Budoff, Matthew J.; Carr, John Jeffrey; Chen, Yii-Der I.; Taylor, Kent D.; Oliveri, Antonino; Correa, Adolfo; Crudup, Breland F.; Kardia, Sharon L. R.; Mosley, Thomas H.; Norris, Jill M.; Terry, James G.; Rotter, Jerome I.; Wagenknecht, Lynne E.; Halligan, Brian D.; Young, Kendra A.; Hokanson, John E.; Washko, George R.; Gudnason, Vilmundur; Province, Michael A.; Peyser, Patricia A.; Palmer, Nicholette D.; Speliotes, Elizabeth K.
Source
Nature Genetics; October 2023, Vol. 55 Issue: 10 p1640-1650, 11p
Subject
Language
ISSN
10614036; 15461718
Abstract
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.