title: Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.
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.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States of America. espeliot@med.umich.edu
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernaez
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Kim
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Palmer
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Garcia
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Clark
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Johannah L
authors.initials: JL
authors.lastname: Butler
authors.forename: Marta
authors.initials: M
authors.lastname: Tomas
authors.forename: Udo
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Massaro
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Dushyant V
authors.initials: DV
authors.lastname: Sahani
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Carr
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D016022:Case-Control Studies; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D015331:Cohort Studies; D005234:Fatty Liver / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000097:blood; D037181:Lectins, C-Type / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014057:Tomography, X-Ray Computed; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D011508:Chondroitin Sulfate Proteoglycans; D007328:Insulin; D037181:Lectins, C-Type; D008049:Lipase; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D058580:Neurocan; C485100:GCKR protein, human; C076817:NCAN protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent