Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

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  • Amit D Joshi
  • Charlotte Andersson
  • Stephan Buch
  • Stefan Stender
  • Raymond Noordam
  • Lu-Chen Weng
  • Peter E Weeke
  • Paul L Auer
  • Bernhard Boehm
  • Constance Chen
  • Hyon Choi
  • Gary Curhan
  • Joshua C Denny
  • Immaculata De Vivo
  • John D Eicher
  • David Ellinghaus
  • Aaron R Folsom
  • Charles Fuchs
  • Manish Gala
  • Jeffrey Haessler
  • Albert Hofman
  • Frank Hu
  • David J Hunter
  • Harry L A Janssen
  • Jae H Kang
  • Charles Kooperberg
  • Peter Kraft
  • Wolfgang Kratzer
  • Wolfgang Lieb
  • Pamela L Lutsey
  • Sarwa Darwish Murad
  • Louis R Pasquale
  • Alex P Reiner
  • Paul M Ridker
  • Eric Rimm
  • Lynda M Rose
  • Christian M Shaffer
  • Clemens Schafmayer
  • Rulla M Tamimi
  • Andre G Uitterlinden
  • Uwe Völker
  • Henry Völzke
  • Yoshiyuki Wakabayashi
  • Janey L. Wiggs
  • Jun Zhu
  • Dan M Roden
  • Bruno H Ch Stricker
  • Weihong Tang
  • Alexander Teumer
  • Jochen Hampe
  • Daniel I Chasman
  • Andrew T Chan
  • Andrew D Johnson

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.

METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.

RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.

CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

Original languageEnglish
Issue number2
Number of pages351
Publication statusPublished - Aug 2016

    Research areas

  • Journal Article

ID: 176827405