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

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 HaesslerAlbert 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, Børge G. Nordestgaard, Louis R. Pasquale, Alex P. Reiner, Paul M. Ridker, Eric Rimm, Lynda M. Rose, Christian M. Shaffer, Clemens Schafmayer, Rulla M. Tamimi, André G. Uitterlinden, Uwe Völker, Henry Völzke, Yoshiyuki Wakabayashi, Janey L. Wiggs, Jun Zhu, Dan M. Roden, Bruno H. Stricker, Weihong Tang, Alexander Teumer, Jochen Hampe, Anne Tybjærg-Hansen, Daniel I. Chasman, Andrew T. Chan, Andrew D. Johnson

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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 (US)
Pages (from-to)351-363.e28
JournalGastroenterology
Volume151
Issue number2
DOIs
StatePublished - Aug 1 2016

Bibliographical note

Funding Information:
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and the US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

Publisher Copyright:
© 2016 AGA Institute

Keywords

  • GWAS
  • Genetics
  • Risk Factors
  • SNP

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