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

Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Mary F. Feitosa, Lawrence F. Bielak, Jeffrey R. O’Connell, Solomon K. Musani, Xiuqing Guo, Bratati Kahali, Vincent L. Chen, Albert V. Smith, Kathleen A. Ryan, Gudny Eirksdottir, Matthew A. Allison, Donald W. Bowden, Matthew J. Budoff, John Jeffrey Carr, Yii Der I. Chen, Kent D. Taylor, Antonino OliveriAdolfo Correa, Breland F. Crudup, Sharon L.R. Kardia, Thomas H. Mosley, Jill M. Norris, James G. Terry, Jerome I. Rotter, Lynne E. Wagenknecht, Brian D. Halligan, Kendra A. Young, John E. Hokanson, George R. Washko, Vilmundur Gudnason, Michael A. Province, Patricia A. Peyser, Nicholette D. Palmer, Elizabeth K. Speliotes

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)1640-1650
Number of pages11
JournalNature Genetics
Volume55
Issue number10
DOIs
StatePublished - Oct 2023

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