Journal Article

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

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

2023

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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