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

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

doi:10.1038/s41588-023-01497-6

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

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

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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.

Original language	English
Pages (from-to)	1640-1650
Number of pages	11
Journal	Nature Genetics
Volume	55
Issue number	10
DOIs	https://doi.org/10.1038/s41588-023-01497-6
State	Published - Oct 2023

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Chen, Y., Du, X., Kuppa, A., Feitosa, M. F., Bielak, L. F., O’Connell, J. R., Musani, S. K., Guo, X., Kahali, B., Chen, V. L., Smith, A. V., Ryan, K. A., Eirksdottir, G., Allison, M. A., Bowden, D. W., Budoff, M. J., Carr, J. J., Chen, Y. D. I., Taylor, K. D., ... Speliotes, E. K. (2023). Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nature Genetics, 55(10), 1640-1650. https://doi.org/10.1038/s41588-023-01497-6

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title = "Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = oct,

doi = "10.1038/s41588-023-01497-6",

language = "English",

volume = "55",

pages = "1640--1650",

journal = "Nature Genetics",

issn = "1061-4036",

number = "10",

}

Chen, Y, Du, X, Kuppa, A, Feitosa, MF, Bielak, LF, O’Connell, JR, Musani, SK, Guo, X, Kahali, B, Chen, VL, Smith, AV, Ryan, KA, Eirksdottir, G, Allison, MA, Bowden, DW, Budoff, MJ, Carr, JJ, Chen, YDI, Taylor, KD, Oliveri, A, Correa, A, Crudup, BF, Kardia, SLR, Mosley, TH, Norris, JM, Terry, JG, Rotter, JI, Wagenknecht, LE, Halligan, BD, Young, KA, Hokanson, JE, Washko, GR, Gudnason, V, Province, MA, Peyser, PA, Palmer, ND & Speliotes, EK 2023, 'Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease', Nature Genetics, vol. 55, no. 10, pp. 1640-1650. https://doi.org/10.1038/s41588-023-01497-6

TY - JOUR

T1 - Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease

AU - Chen, Yanhua

AU - Du, Xiaomeng

AU - Kuppa, Annapurna

AU - Feitosa, Mary F.

AU - Bielak, Lawrence F.

AU - O’Connell, Jeffrey R.

AU - Musani, Solomon K.

AU - Guo, Xiuqing

AU - Kahali, Bratati

AU - Chen, Vincent L.

AU - Smith, Albert V.

AU - Ryan, Kathleen A.

AU - Eirksdottir, Gudny

AU - Allison, Matthew A.

AU - Bowden, Donald W.

AU - Budoff, Matthew J.

AU - Carr, John Jeffrey

AU - Chen, Yii Der I.

AU - Taylor, Kent D.

AU - Oliveri, Antonino

AU - Correa, Adolfo

AU - Crudup, Breland F.

AU - Kardia, Sharon L.R.

AU - Mosley, Thomas H.

AU - Norris, Jill M.

AU - Terry, James G.

AU - Rotter, Jerome I.

AU - Wagenknecht, Lynne E.

AU - Halligan, Brian D.

AU - Young, Kendra A.

AU - Hokanson, John E.

AU - Washko, George R.

AU - Gudnason, Vilmundur

AU - Province, Michael A.

AU - Peyser, Patricia A.

AU - Palmer, Nicholette D.

AU - Speliotes, Elizabeth K.

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

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U2 - 10.1038/s41588-023-01497-6

DO - 10.1038/s41588-023-01497-6

M3 - Article

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AN - SCOPUS:85171286770

SN - 1061-4036

VL - 55

SP - 1640

EP - 1650

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

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