Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

被引：767

作者：

Speliotes, Elizabeth K. ^{[1
,2
,3
,4
]}

Yerges-Armstrong, Laura M. ^{[5
]}

Wu, Jun ^{[6
]}

Hernaez, Ruben ^{[7
,8
,9
]}

Kim, Lauren J. ^{[10
]}

Palmer, Cameron D. ^{[11
,12
,13
]}

Gudnason, Vilmundur ^{[14
,15
]}

Eiriksdottir, Gudny ^{[14
]}

Garcia, Melissa E. ^{[10
]}

Launer, Lenore J. ^{[10
]}

Nalls, Michael A. ^{[16
]}

Clark, Jeanne M. ^{[7
,8
,17
]}

Mitchell, Braxton D. ^{[5
]}

Shuldiner, Alan R. ^{[5
,18
]}

Butler, Johannah L. ^{[1
,2
,11
,12
,13
]}

Tomas, Marta ^{[19
,20
]}

Hoffmann, Udo ^{[21
,22
]}

Hwang, Shih-Jen ^{[23
]}

Massaro, Joseph M. ^{[23
,24
]}

O'Donnell, Christopher J. ^{[22
,23
,25
]}

Sahani, Dushyant V. ^{[21
]}

Salomaa, Veikko ^{[26
]}

Schadt, Eric E. ^{[27
]}

Schwartz, Stephen M. ^{[28
,29
]}

Siscovick, David S. ^{[28
,29
]}

Voight, Benjamin F. ^{[4
]}

Carr, J. Jeffrey ^{[30
,31
,32
]}

Feitosa, Mary F. ^{[6
]}

Harris, Tamara B. ^{[10
]}

Fox, Caroline S. ^{[23
,25
]}

Smith, Albert V. ^{[14
]}

Kao, W. H. Linda ^{[7
,17
]}

Hirschhorn, Joel N. ^{[4
,11
,12
,13
,33
]}

Borecki, Ingrid B. ^{[6
]}

机构：

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

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

[3] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[4] Broad Inst, Cambridge, MA USA

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

[6] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[7] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[8] Johns Hopkins Univ Hosp, Div Gen Internal Med, Baltimore, MD 21287 USA

[9] Washington Hosp Ctr, Dept Internal Med, Washington, DC USA

[10] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA

[11] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[12] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[13] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[14] Iceland Heart Assoc, Kopavogur, Iceland

[15] Univ Iceland, Reykjavik, Iceland

[16] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[17] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA

[18] Vet Adm Med Ctr, GRECC, Baltimore, MD 21218 USA

[19] Inst Municipal Invest Med, E-08003 Barcelona, Spain

[20] CIBER Epidemiol & Salud Publ, Barcelona, Spain

[21] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA

[22] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[23] NHLBI, Framingham Heart Study, Framingham, MA USA

[24] Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA

[25] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA

[26] Natl Publ Hlth Inst, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland

[27] Pacific Biosci, Menlo Pk, CA USA

[28] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[29] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[30] Wake Forest Univ Sch Med, Dept Radiol Sci, Winston Salem, NC USA

[31] Wake Forest Univ Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA

[32] Wake Forest Univ Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA

[33] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

来源：

PLOS GENETICS | 2011年 / 7卷 / 03期

基金：

美国国家卫生研究院;

关键词：

LOCI; HEART; RISK; STEATOHEPATITIS; PNPLA3; SUSCEPTIBILITY; GLUCOKINASE; STEATOSIS; GLUCOSE; DESIGN;

D O I：

10.1371/journal.pgen.1001324

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (similar to 26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and similar to 2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<56 10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

引用

页数：14

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