title: Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent.
abstract: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age(2) , gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2) , respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
  
  
  CONCLUSIONS
  Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: Solomon K
authors.initials: SK
authors.lastname: Musani
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Bielak
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernaez
authors.forename: Bratati
authors.initials: B
authors.lastname: Kahali
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Carr
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Min A
authors.initials: MA
authors.lastname: Jhun
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Peyser
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D044383:Black People / Q000208:ethnology / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D015331:Cohort Studies; D005234:Fatty Liver / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006630:Hispanic or Latino / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008245:Lysophospholipase / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D044465:White People / Q000208:ethnology / Q000235:genetics*; D001741:Black or African American; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D008049:Lipase; D008245:Lysophospholipase; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D058580:Neurocan; D010749:Phosphoprotein Phosphatases; C485100:GCKR protein, human; C076817:NCAN protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent; C561408:LYPLAL1 protein, human; C114205:PPP1R3A protein, human
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