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

NASH CRN, GIANT Consortium, MAGIC Investigators, GOLD Consortium, MAGIC, on behalf of Procardis Consortium, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium

Research output: Contribution to journalArticle

443 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1001324
JournalPLoS Genetics
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

Fingerprint

Genome-Wide Association Study
fatty liver
genome
tomography
Tomography
Amish
Liver
computed tomography
Single Nucleotide Polymorphism
serum
heart
lipid
Genome
Lipids
Genetic Heterogeneity
meta-analysis
abnormality
blood lipids
Serum
Meta-Analysis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

NASH CRN, GIANT Consortium, MAGIC Investigators, GOLD Consortium, MAGIC, on behalf of Procardis Consortium, ... Global BPgen Consortium (2011). Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genetics, 7(3), [e1001324]. https://doi.org/10.1371/journal.pgen.1001324

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. / NASH CRN; GIANT Consortium; MAGIC Investigators; GOLD Consortium; MAGIC; on behalf of Procardis Consortium; DIAGRAM Consortium; GIANT Consortium; Global BPgen Consortium.

In: PLoS Genetics, Vol. 7, No. 3, e1001324, 01.03.2011.

Research output: Contribution to journalArticle

NASH CRN, GIANT Consortium, MAGIC Investigators, GOLD Consortium, MAGIC, on behalf of Procardis Consortium, DIAGRAM Consortium, GIANT Consortium & Global BPgen Consortium 2011, 'Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits', PLoS Genetics, vol. 7, no. 3, e1001324. https://doi.org/10.1371/journal.pgen.1001324
NASH CRN, GIANT Consortium, MAGIC Investigators, GOLD Consortium, MAGIC, on behalf of Procardis Consortium et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genetics. 2011 Mar 1;7(3). e1001324. https://doi.org/10.1371/journal.pgen.1001324
NASH CRN ; GIANT Consortium ; MAGIC Investigators ; GOLD Consortium ; MAGIC ; on behalf of Procardis Consortium ; DIAGRAM Consortium ; GIANT Consortium ; Global BPgen Consortium. / Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. In: PLoS Genetics. 2011 ; Vol. 7, No. 3.
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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.",
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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 - Global BPgen Consortium

AU - Speliotes, Elizabeth K.

AU - Yerges-Armstrong, Laura M.

AU - Wu, Jun

AU - Hernaez, Ruben

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AU - Gudnason, Vilmundur

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AU - Clark, Jeanne M.

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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

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AU - Cummings, Oscar

AU - Molleston, Jean

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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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