Chen, Y and Du, X and Kuppa, A and Feitosa, MF and Bielak, LF and O�Connell, JR and Musani, SK and Guo, X and Kahali, B and Chen, VL and Smith, AV and Ryan, KA and Eirksdottir, G and Allison, MA and Bowden, DW and Budoff, MJ and Carr, JJ and Chen, Y-DI and Taylor, KD and Oliveri, A and Correa, A and Crudup, BF and Kardia, SLR and Mosley, Jr and Norris, JM and Terry, JG and Rotter, JI and Wagenknecht, LE and Halligan, BD and Young, KA and Hokanson, JE and Washko, GR and Gudnason, V and Province, MA and Peyser, PA and Palmer, ND and Speliotes, EK (2023) Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. In: Nature Genetics, 55 (10). pp. 1640-1650.
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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. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
| Item Type: | Journal Article |
|---|---|
| Publication: | Nature Genetics |
| Publisher: | Nature Research |
| Additional Information: | The copyright for this article belongs to authors. |
| Keywords: | alanine aminotransferase; alcohol dehydrogenase; alcohol dehydrogenase1b; alpha ketoglutarate dependent dioxygenase FTO; apolipoprotein E; cholesterol; cordon bleu WH2 repeat protein like 1; glucokinase regulator; glycerol 3 phosphate acyltransferase; growth factor receptor bound protein 14; high density lipoprotein cholesterol; insulin receptor; low density lipoprotein cholesterol; membrane bound o acyltransferase domain containing 7; microsomal triglyceride transfer protein; mitochondrial amidoxime reducing component 1; patatin like phospholipase domain containing protein 2; receptor type tyrosine protein phosphatase delta; sex hormone binding protein; somatomedin C; sterol regulatory element binding protein 1; torsin family 1 member B; transmembrane 6 superfamily 2; transmembrane channel like 4; triacylglycerol; tribbles homolog1; unclassified drug; acyltransferase; alpha ketoglutarate dependent dioxygenase FTO; FTO protein, human; phospholipase; protein serine threonine kinase; signal peptide; TRIB1 protein, human, adult; alcohol consumption; ancestry group; Article; Chinese; cholelithiasis; cholesterol blood level; controlled study; disease predisposition; esophagus varices; female; gene expression; gene locus; genetic risk; genetic risk score; genetic variability; genome-wide association study; heavy drinking; Hispanic; human; lipogenesis; liver cell carcinoma; liver cirrhosis; major clinical study; male; Mendelian randomization analysis; nonalcoholic fatty liver; pathway analysis; phenotype; quantitative trait locus; risk assessment; complication; genetic predisposition; genetics; genome-wide association study; liver; meta analysis; metabolism; nonalcoholic fatty liver; single nucleotide polymorphism, Acyltransferases; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Intracellular Signaling Peptides and Proteins; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Phospholipases; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases |
| Department/Centre: | Autonomous Societies / Centres > Centre for Brain Research |
| Date Deposited: | 13 Dec 2024 18:00 |
| Last Modified: | 13 Dec 2024 18:00 |
| URI: | http://eprints.iisc.ac.in/id/eprint/85417 |
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