TY - JOUR
T1 - Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
AU - Global-BPGen Consortium
AU - NASH CRN
AU - GIANT Consortium
AU - MAGIC Investigators
AU - GOLD Consortium
AU - MAGIC
AU - on behalf of Procardis Consortium
AU - DIAGRAM Consortium
AU - GIANT Consortium
AU - Speliotes, Elizabeth K.
AU - Yerges-Armstrong, Laura M.
AU - Wu, Jun
AU - Hernaez, Ruben
AU - Kim, Lauren J.
AU - Palmer, Cameron D.
AU - Gudnason, Vilmundur
AU - Eiriksdottir, Gudny
AU - Garcia, Melissa E.
AU - Launer, Lenore J.
AU - Nalls, Michael A.
AU - Clark, Jeanne M.
AU - Mitchell, Braxton D.
AU - Shuldiner, Alan R.
AU - Butler, Johannah L.
AU - Tomas, Marta
AU - Hoffmann, Udo
AU - Hwang, Shih Jen
AU - Massaro, Joseph M.
AU - O'Donnell, Christopher J.
AU - Sahani, Dushyant V.
AU - Salomaa, Veikko
AU - Schadt, Eric E.
AU - Schwartz, Stephen M.
AU - Siscovick, David S.
AU - Voight, Benjamin F.
AU - Jeffrey Carr, J.
AU - Feitosa, Mary F.
AU - Harris, Tamara B.
AU - Fox, Caroline S.
AU - Smith, Albert V.
AU - Linda Kao, W. H.
AU - Hirschhorn, Joel N.
AU - Borecki, Ingrid B.
AU - McCullough, Arthur
AU - Bringman, Diane
AU - Dasarathy, Srinivasan
AU - Edwards, Kevin
AU - Hawkins, Carol
AU - Liu, Yao Chang
AU - Rogers, Nicholette
AU - Ruth Sargent, P. A.C.
AU - Stager, Margaret
AU - Diehl, Anna Mae
AU - Abdelmalek, Manal
AU - Gottfried, Marcia
AU - Guy, Cynthia
AU - Killenberg, Paul
AU - Kwan, Samantha
AU - Kaplan, Robert C.
N1 - Publisher Copyright:
© 2011, Public Library of Science. All Rights Reserved.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1001324
DO - 10.1371/journal.pgen.1001324
M3 - Article
C2 - 21423719
AN - SCOPUS:79953745343
SN - 1553-7390
VL - 7
JO - PLoS genetics
JF - PLoS genetics
IS - 3
M1 - e1001324
ER -