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Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Publication ,  Journal Article
Speliotes, EK; Yerges-Armstrong, LM; Wu, J; Hernaez, R; Kim, LJ; Palmer, CD; Gudnason, V; Eiriksdottir, G; Garcia, ME; Launer, LJ; Nalls, MA ...
Published in: PLoS Genet
March 2011

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

March 2011

Volume

7

Issue

3

Start / End Page

e1001324

Location

United States

Related Subject Headings

  • Tomography, X-Ray Computed
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Non-alcoholic Fatty Liver Disease
  • Neurocan
  • Nerve Tissue Proteins
  • Mutation, Missense
  • Middle Aged
  • Membrane Proteins
  • Male
 

Citation

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Chicago
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Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., … GOLD Consortium, . (2011). Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet, 7(3), e1001324. https://doi.org/10.1371/journal.pgen.1001324
Speliotes, Elizabeth K., Laura M. Yerges-Armstrong, Jun Wu, Ruben Hernaez, Lauren J. Kim, Cameron D. Palmer, Vilmundur Gudnason, et al. “Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet 7, no. 3 (March 2011): e1001324. https://doi.org/10.1371/journal.pgen.1001324.
Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011 Mar;7(3):e1001324.
Speliotes, Elizabeth K., et al. “Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet, vol. 7, no. 3, Mar. 2011, p. e1001324. Pubmed, doi:10.1371/journal.pgen.1001324.
Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang S-J, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, NASH CRN, GIANT Consortium, MAGIC Investigators, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WHL, Hirschhorn JN, Borecki IB, GOLD Consortium. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011 Mar;7(3):e1001324.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

March 2011

Volume

7

Issue

3

Start / End Page

e1001324

Location

United States

Related Subject Headings

  • Tomography, X-Ray Computed
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Non-alcoholic Fatty Liver Disease
  • Neurocan
  • Nerve Tissue Proteins
  • Mutation, Missense
  • Middle Aged
  • Membrane Proteins
  • Male