Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-wide Association Studies
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Author
Joshi, Amit
Andersson, Charlotte
Buch, Stephan
Stender, Stefan
Noordam, Raymond
Weng, Lu-Chen
Weeke, Peter
Auer, Paul
Boehm, Bernhard
Chen, Constance
Choi, Hyon
Curhan, Gary
Denny, Joshua
De Vivo, Immaculata
Eicher, John
Ellinghaus, David
Folsom, Aaron
Fuchs, Charles
Gala, Manish
Haessler, Jeffrey
Hofman, Albert
Hu, Frank
Hunter, David
Janssen, Harry L. A.
Kang, Jae
Kooperberg, Charles
Kraft, Peter
Kratzer, Wolfgang
Lieb, Wolfgang
Lutsey, Pamela
Murad, Sarwa Darwish
Nordestgaard, Børge G.
Pasquale, Louis
Reiner, Alex
Ridker, Paul
Rimm, Eric Bruce::0ab2926c8242f35e5a982e3cf59f4987::600
Rose, Lynda
Shaffer, Christian
Schafmayer, Clemens
Tamimi, Rulla
Uitterlinden, André G.
Völker, Uwe
Völzke, Henry
Wakabayashi, Yoshiyuki
Wiggs, Janey
Zhu, Jun
Roden, Dan
Stricker, Bruno
Tang, Weihong
Teumer, Alexander
Hampe, Jochen
Tybjærg-Hansen, Anne
Chasman, Daniel
Chan, Andrew
Johnson, Andrew
Published Version
https://doi.org/10.1053/j.gastro.2016.04.007Metadata
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Joshi, Amit D., Charlotte Andersson, Stephan Buch, Stefan Stender, Raymond Noordam, Lu-Chen Weng, Peter E. Weeke, et al. 2016. “Four Susceptibility Loci for Gallstone Disease Identified in a Meta-Analysis of Genome-Wide Association Studies.” Gastroenterology 151 (2): 351–363.e28. https://doi.org/10.1053/j.gastro.2016.04.007.Abstract
BACKGROUND and 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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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.Terms of Use
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