Genome-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...

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Veröffentlicht in:	Nature genetics 2023-10, Vol.55 (10), p.1640-1650
Hauptverfasser:	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.
Format:	Artikel
Sprache:	eng
Schlagworte:	631/208 692/699/1503/1607 Acyltransferase Acyltransferases - genetics Acyltransferases - metabolism Agriculture Alcohol dehydrogenase Alcohol use Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism Animal Genetics and Genomics Apolipoprotein E Apolipoproteins Biomedical and Life Sciences Biomedicine Biosynthesis Body fat Cancer Research Cholesterol Cirrhosis Cobl protein Dehydrogenases Drug development Fatty liver Gene Function Genes Genetic diversity Genetic Predisposition to Disease Genetic variance Genome-wide association studies Genome-Wide Association Study Genomes Genomics Glucokinase Glycerol Glycerol-3-phosphate Growth factors Health risk assessment Health risks Hepatocellular carcinoma Human Genetics Humans Intracellular Signaling Peptides and Proteins - genetics Lipids Lipogenesis Liver Liver - metabolism Liver cancer Liver cirrhosis Liver Cirrhosis - genetics Liver diseases Magnetic resonance imaging Meta-analysis Metabolism Non-alcoholic Fatty Liver Disease - complications Non-alcoholic Fatty Liver Disease - genetics Non-alcoholic Fatty Liver Disease - metabolism Obesity Phosphatase Phospholipase Phospholipases - genetics Polymorphism, Single Nucleotide Protein phosphatase Protein Serine-Threonine Kinases - genetics Protein-tyrosine-phosphatase Proteins Receptors Regulatory sequences Risk Sterols Transcription factors Triglycerides Tyrosine
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Zusammenfassung:	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. Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-023-01497-6