Altmetric

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

Title: Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
Authors: 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, SJ
Massaro, JM
O'Donnell, CJ
Sahani, DV
Salomaa, V
Schadt, EE
Schwartz, SM
Siscovick, DS
Voight, BF
Carr, JJ
Feitosa, MF
Harris, TB
Fox, CS
Smith, AV
Kao, WH
Hirschhorn, JN
Borecki, IB
Item Type: Journal Article
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.
Issue Date: 10-Mar-2011
Date of Acceptance: 2-Feb-2011
URI: http://hdl.handle.net/10044/1/28747
DOI: https://dx.doi.org/10.1371/journal.pgen.1001324
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLOS Genetics
Volume: 7
Issue: 3
Copyright Statement: 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.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: G0801056B
G1000758
G0801056/1
Keywords: Adaptor Proteins, Signal Transducing
Adult
Aged
Aged, 80 and over
Blood Glucose
Case-Control Studies
Chondroitin Sulfate Proteoglycans
Cohort Studies
Fatty Liver
Genome-Wide Association Study
Humans
Insulin
Lectins, C-Type
Lipase
Male
Membrane Proteins
Middle Aged
Mutation, Missense
Nerve Tissue Proteins
Non-alcoholic Fatty Liver Disease
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Tomography, X-Ray Computed
NASH CRN
GIANT Consortium
MAGIC Investigators
GOLD Consortium
Adaptor Proteins, Signal Transducing/genetics Adult Aged Aged, 80 and over Blood Glucose/analysis Case-Control Studies Chondroitin Sulfate Proteoglycans/genetics Cohort Studies Fatty Liver/*genetics/metabolism/radiography Genome-Wide Association Study Humans Insulin/blood Lectins, C-Type/genetics Lipase/genetics Male Membrane Proteins/genetics Middle Aged Mutation, Missense Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Tomography, X-Ray Computed
Developmental Biology
0604 Genetics
Notes: Speliotes, Elizabeth K Yerges-Armstrong, Laura M Wu, Jun Hernaez, Ruben Kim, Lauren J Palmer, Cameron D Gudnason, Vilmundur Eiriksdottir, Gudny Garcia, Melissa E Launer, Lenore J Nalls, Michael A Clark, Jeanne M Mitchell, Braxton D Shuldiner, Alan R Butler, Johannah L Tomas, Marta Hoffmann, Udo Hwang, Shih-Jen Massaro, Joseph M O'Donnell, Christopher J Sahani, Dushyant V Salomaa, Veikko Schadt, Eric E Schwartz, Stephen M Siscovick, David S Nash crn GIANT Consortium MAGIC Investigators Voight, Benjamin F Carr, J Jeffrey Feitosa, Mary F Harris, Tamara B Fox, Caroline S Smith, Albert V Kao, W H Linda Hirschhorn, Joel N Borecki, Ingrid B GOLD Consortium F32 DK079466-01/DK/NIDDK NIH HHS/United States F32AR059469/AR/NIAMS NIH HHS/United States K01 DK067207/DK/NIDDK NIH HHS/United States K23DK080145-01/DK/NIDDK NIH HHS/United States M01RR000065/RR/NCRR NIH HHS/United States M01RR000750/RR/NCRR NIH HHS/United States M01RR000827/RR/NCRR NIH HHS/United States M01RR00188/RR/NCRR NIH HHS/United States M01RR020359/RR/NCRR NIH HHS/United States N01-AG-12100/AG/NIA NIH HHS/United States N01-HC-25195/HC/NHLBI NIH HHS/United States N02-HL-6-4278/HL/NHLBI NIH HHS/United States P30DK072488/DK/NIDDK NIH HHS/United States P60 DK079637/DK/NIDDK NIH HHS/United States R01 AG18728/AG/NIA NIH HHS/United States R01DK075681/DK/NIDDK NIH HHS/United States R01DK075787/DK/NIDDK NIH HHS/United States R01HL087700/HL/NHLBI NIH HHS/United States R01HL088119/HL/NHLBI NIH HHS/United States T32 DK07191-32/DK/NIDDK NIH HHS/United States T32AG000262/AG/NIA NIH HHS/United States U01 HL084756/HL/NHLBI NIH HHS/United States U01 HL72515/HL/NHLBI NIH HHS/United States U01DK061713/DK/NIDDK NIH HHS/United States U01DK061718/DK/NIDDK NIH HHS/United States U01DK061728/DK/NIDDK NIH HHS/United States U01DK061730/DK/NIDDK NIH HHS/United States U01DK061731/DK/NIDDK NIH HHS/United States U01DK061732/DK/NIDDK NIH HHS/United States U01DK061734/DK/NIDDK NIH HHS/United States U01DK061737/DK/NIDDK NIH HHS/United States U01DK061738/DK/NIDDK NIH HHS/United States UL1RR024989/RR/NCRR NIH HHS/United States UL1RR02501401/RR/NCRR NIH HHS/United States ULRR02413101/PHS HHS/United States Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't United States PLoS genetics PLoS Genet. 2011 Mar;7(3):e1001324. Epub 2011 Mar 10. 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 ( approximately 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 approximately 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<5x10(-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.
Publication Status: Published
Article Number: e1001324
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commons