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Elizabeth K Speliotes; Laura M Yerges-Armstrong; Jun Wu; Ruben Hernaez; Lauren J Kim; Cameron D Palmer; Vilmundur Gudnason; Gudny Eiriksdottir; Melissa E Garcia; Lenore J Launer; Michael A Nalls; Jeanne M Clark; Braxton D Mitchell; Alan R Shuldiner; Johannah L Butler; Marta Tomas; Udo Hoffmann; Shih-Jen Hwang; Joseph M Massaro; Christopher J O'Donnell; Dushyant V Sahani; Veikko Salomaa; Eric E Schadt; Stephen M Schwartz; David S Siscovick; Benjamin F Voight; J Jeffrey Carr; Mary F Feitosa; Tamara B Harris; Caroline S Fox ... view all 34 authors View less authors (2011)
Publisher: Public Library of Science (PLoS)
Journal: PLoS Genetics
Languages: English
Types: Article
Subjects: 3141 Health care science, Research Article, Diabetes and Endocrinology/Obesity, coronary-artery-disease ; triglyceride levels ; loci ; heart ; risk ; design ; adults ; steatohepatitis ; PNPLA3 ; susceptibility, hepatology, Gastroenterology and Hepatology/Hepatology, gastroenterology, genetics and genomics, QH426-470, Genetics, Settore MED/14 - Nefrologia, Genetics and Genomics/Complex Traits, diabetes, obesity, endocrinology
: 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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Funded by projects

  • NIH | NASH PROJECT
  • NIH | Genetic Influences on Coron...
  • NIH | Genetic Epidemiology of Met...
  • NIH | Continuation of the Nonalco...
  • NIH | Research Training in Digest...
  • NIH | Research Training in the Ep...
  • NIH | CASE WESTERN RESERVE UNIVER...
  • NIH | Genetic Epidemiology of NAF...
  • NIH | AGES STUDY-THE REYKJAVIK ST...
  • NIH | Collaborative Clinical Rese...
  • NIH | FHS-SCAN Genome Wide Associ...
  • NIH | CHOLESTEROL METABOLISM IN T...
  • NIH | The Saint Louis University ...
  • NIH | Analysis of Fatty Liver in ...
  • NIH | THE FRAMINGHAM HEART STUDY-...
  • NIH | CANDIDATE GENE STUDIES OF O...
  • NIH | Pathogenesis, prognosis, an...
  • NIH | Genome-wide Search for CVD ...
  • NIH | Analysis of Fatty Liver in ...
  • NIH | ABT378/RITONAVIR IN COMBINA...
  • NIH | Nonalcoholic Steatohepatiti...
  • NIH | CORE--ADIPOSE TISSUE BIOLOG...
  • NIH | Clinical Research on Nonalc...
  • NIH | Clinical Research Network i...
  • NIH | Clinical Research Network i...
  • NIH | Diabetes Research and Train...
  • NIH | GENERAL CLINICAL RESEARCH C...
  • NIH | EVALUATION OF ORAL ZIDOVUDI...
  • NIH | NEURODEVELOPMENTAL OUTCOME ...
  • NIH | Longevity Genes in Founder ...
  • NIH | Genome-wide Association in ...
  • NIH | Genetics of Bone Mineral De...

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