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

被引：84

作者：

Chen, Yanhua ^{[1
,2
]}

Du, Xiaomeng ^{[1
,2
]}

Kuppa, Annapurna ^{[1
,2
]}

Feitosa, Mary F. ^{[3
]}

Bielak, Lawrence F. ^{[4
]}

O'Connell, Jeffrey R. ^{[5
]}

Musani, Solomon K. ^{[6
]}

Guo, Xiuqing ^{[7
]}

Kahali, Bratati ^{[1
,2
,8
]}

Chen, Vincent L. ^{[1
,2
]}

Smith, Albert V. ^{[9
]}

Ryan, Kathleen A. ^{[5
]}

Eirksdottir, Gudny ^{[10
]}

Allison, Matthew A. ^{[11
]}

Bowden, Donald W. ^{[12
]}

Budoff, Matthew J. ^{[13
]}

Carr, John Jeffrey ^{[14
]}

Chen, Yii-Der I. ^{[7
]}

Taylor, Kent D. ^{[7
]}

Oliveri, Antonino ^{[1
,2
]}

Correa, Adolfo ^{[6
]}

Crudup, Breland F. ^{[6
]}

Kardia, Sharon L. R. ^{[4
]}

Mosley, Thomas H. ^{[6
]}

Norris, Jill M. ^{[15
]}

Terry, James G. ^{[14
]}

Rotter, Jerome I. ^{[7
]}

Wagenknecht, Lynne E. ^{[16
]}

Halligan, Brian D. ^{[1
,2
]}

Young, Kendra A. ^{[15
]}

Hokanson, John E. ^{[15
]}

Washko, George R. ^{[17
]}

Gudnason, Vilmundur ^{[10
,18
]}

Province, Michael A. ^{[3
]}

Peyser, Patricia A. ^{[4
]}

Palmer, Nicholette D. ^{[12
]}

Speliotes, Elizabeth K. ^{[1
,2
]}

机构：

[1] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[3] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO USA

[4] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI USA

[5] Univ Maryland Baltimore, Dept Endocrinol Diabet & Nutr, Baltimore, MD USA

[6] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA

[7] UCLA Med Ctr, Inst Translat Genom & Populat Sci, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA

[8] Indian Inst Sci, Ctr Brain Res, Bangalore, India

[9] Univ Michigan, Dept Biostat, Ann Arbor, MI USA

[10] Iceland Heart Assoc, Kopavogur, Iceland

[11] Univ Calif San Diego, Dept Family Med, San Diego, CA USA

[12] Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA

[13] UCLA, Lundquist Inst Harbor, Dept Internal Med, Torrance, CA USA

[14] Vanderbilt Univ, Dept Radiol, Dept Radiol, Nashville, TN USA

[15] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA

[16] Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA

[17] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA USA

[18] Univ Iceland, Dept Med, Reykjavik, Iceland

来源：

NATURE GENETICS | 2023年 / 55卷 / 10期

基金：

美国国家卫生研究院;

关键词：

REGULATES HEPATIC LIPOGENESIS; MENDELIAN RANDOMIZATION; GENETIC-VARIANTS; CONFERS SUSCEPTIBILITY; HYPERTENSION TREATMENT; GLUCOSE-HOMEOSTASIS; INSULIN-RESISTANCE; METABOLIC SYNDROME; UNITED-STATES; RISK;

D O I：

10.1038/s41588-023-01497-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 & delta; (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.

引用

页码：1640 / 1650

页数：11

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