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Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
PLoS Genet 2011; 7(3):e1001324PG

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.

Authors+Show Affiliations

Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States of America. espeliot@med.umich.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21423719

Citation

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 Genetics, vol. 7, no. 3, 2011, pp. e1001324.
Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324.
Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., ... Borecki, I. B. (2011). Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genetics, 7(3), pp. e1001324. doi:10.1371/journal.pgen.1001324.
Speliotes EK, et al. Genome-wide Association Analysis Identifies Variants Associated With Nonalcoholic Fatty Liver Disease That Have Distinct Effects On Metabolic Traits. PLoS Genet. 2011;7(3):e1001324. PubMed PMID: 21423719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. 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 - ,, AU - ,, AU - ,, AU - Voight,Benjamin F, AU - Carr,J Jeffrey, AU - Feitosa,Mary F, AU - Harris,Tamara B, AU - Fox,Caroline S, AU - Smith,Albert V, AU - Kao,W H Linda, AU - Hirschhorn,Joel N, AU - Borecki,Ingrid B, AU - ,, Y1 - 2011/03/10/ PY - 2010/06/18/received PY - 2011/02/02/accepted PY - 2011/3/23/entrez PY - 2011/3/23/pubmed PY - 2011/8/30/medline SP - e1001324 EP - e1001324 JF - PLoS genetics JO - PLoS Genet. VL - 7 IS - 3 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. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/21423719/Genome_wide_association_analysis_identifies_variants_associated_with_nonalcoholic_fatty_liver_disease_that_have_distinct_effects_on_metabolic_traits_ L2 - http://dx.plos.org/10.1371/journal.pgen.1001324 DB - PRIME DP - Unbound Medicine ER -