- Chen, Yanhua;
- Du, Xiaomeng;
- Kuppa, Annapurna;
- Feitosa, Mary;
- Bielak, Lawrence;
- OConnell, Jeffrey;
- Musani, Solomon;
- Guo, Xiuqing;
- Kahali, Bratati;
- Chen, Vincent;
- Smith, Albert;
- Ryan, Kathleen;
- Eirksdottir, Gudny;
- Allison, Matthew;
- Bowden, Donald;
- Budoff, Matthew;
- Carr, John;
- Chen, Yii-Der;
- Taylor, Kent;
- Oliveri, Antonino;
- Correa, Adolfo;
- Crudup, Breland;
- Kardia, Sharon;
- Mosley, Thomas;
- Norris, Jill;
- Terry, James;
- Rotter, Jerome;
- Wagenknecht, Lynne;
- Halligan, Brian;
- Young, Kendra;
- Hokanson, John;
- Washko, George;
- Gudnason, Vilmundur;
- Province, Michael;
- Peyser, Patricia;
- Palmer, Nicholette;
- Speliotes, Elizabeth
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.