biostudies-literatureChen YNCATS NIH HHSNIDDK NIH HHSNIDA NIH HHSNIA NIH HHSNHLBI NIH HHSNIMHD NIH HHSU.S. Department of Health & Human Services | National Institutes of Health1640-1650https://www.ebi.ac.uk/biostudies/studies/S-EPMC10918428biostudies-literatureUnknown55(10)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.Nature geneticsGenome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.PMC10918428U01 HL084756UL1 TR001881N01 HC095166N01 HC095165N01 HC095168N01 HC095167R01 HL060944HHSN268201800014CN01 HC095169R01 DK131787R01 DK106621N01 HC095160P30 DK072488U01 HL089897N01 HC095162N01 HC095161N01 HC095164U01 HL089856HHSN268201800014IN01 HC095163R01 HL085571HHSN268201800010IHHSN268201500001CUL1 TR000040R01 HL060919N02 HL064278N01AG12100R01 HL087700R01 HL061019R01 DK089256R01 HL117078HHSN268201800013IR01 HL087660P30 DK063491HHSN268201500001IR01 HL061210RC1 HL100245UL1 TR001420R01 DK085175R01 DK128871N01 HC025195R01 HL06089475N92020D00007HHSN268201800012CU01 HL072515HHSN268201800012I75N92019D0003175N92020D0000175N92020D00002R01 HL122464R01 DK11806275N92020D0000575N92020D00006R01 HL07173975N92020D0000375N92020D00004HHSN268201500003CUL1 TR001079R01 DK106621, RO1 DK107904N01 HC095159U01 HL137181HHSN271201200022CHHSN268201800015IHHSN268201800011CHHSN268201800011IR01 HL105756R01 DK107904HHSN268201500003IKuppa AHalligan BDBowden DWKardia SLRRotter JIProvince MAGuo XWashko GRFeitosa MFDu XCorrea AGudnason VBielak LFHokanson JESpeliotes EKBudoff MJWagenknecht LEChen VLMosley THAllison MAChen YSmith AVO'Connell JRRyan KACarr JJTaylor KDMusani SKTerry JGPalmer NDEirksdottir GKahali BOliveri AChen YIPeyser PACrudup BFYoung KANorris JMfalseGenome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.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.2023-01-01T00:00:00Z2023 Oct2026-05-29T10:04:36.624Z2025-04-07T02:08:02.918ZS-EPMC109184283770986410.1038/s41588-023-01497-6