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Type: Journal article
Title: Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
Author: Speliotes, E.
Yerges-Armstrong, L.
Wu, J.
Hernaez, R.
Kim, L.
Palmer, C.
Gudnason, V.
Eiriksdottir, G.
Garcia, M.
Launer, L.
Nalls, M.
Clark, J.
Mitchell, B.
Shuldiner, A.
Butler, J.
Tomas, M.
Hoffmann, U.
Hwang, S.
Massaro, J.
O’Donnell, C.
et al.
Citation: PLoS Genetics, 2011; 7(3):e1001324-1-e1001324-14
Publisher: Public Library of Science
Issue Date: 2011
ISSN: 1553-7390
Editor: McCarthy, M.I.
Statement of
Elizabeth K. Speliotes, Laura M. Yerges-Armstrong, Jun Wu, Ruben Hernaez, Lauren J. Kim, Cameron D. Palmer, Vilmundur Gudnason, Gudny Eiriksdottir, Melissa E. Garcia, Lenore J. Launer, Michael A. Nalls, Jeanne M. Clark, Braxton D. Mitchell, Alan R. Shuldiner, Johannah L. Butler, Marta Tomas, Udo Hoffmann, Shih-Jen Hwang, Joseph M. Massaro, Christopher J. O, Donnell, Dushyant V. Sahani, Veikko Salomaa, Eric E. Schadt, Stephen M. Schwartz, David S. Siscovick, NASH CRN, GIANT Consortium, MAGIC Investigators, Benjamin F. Voight, J. Jeffrey Carr, Mary F. Feitosa, Tamara B. Harris, Caroline S. Fox, Albert V. Smith, W. H. Linda Kao, Joel N. Hirschhorn, Ingrid B. Borecki, GOLD Consortium
Abstract: 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 (∼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 ∼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<5×10−8) 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.
Keywords: NASH CRN
GIANT Consortium
MAGIC Investigators
GOLD Consortium
Fatty Liver
Blood Glucose
Adaptor Proteins, Signal Transducing
Lectins, C-Type
Membrane Proteins
Nerve Tissue Proteins
Tomography, X-Ray Computed
Case-Control Studies
Cohort Studies
Mutation, Missense
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Aged, 80 and over
Middle Aged
Genome-Wide Association Study
Chondroitin Sulfate Proteoglycans
Non-alcoholic Fatty Liver Disease
Description: Lyle J Palmer is a member of the GIANT Consortium
Rights: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
DOI: 10.1371/journal.pgen.1001324
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