TY - JOUR

T1 - Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

AU - Joshi, Amit D

AU - Andersson, Charlotte

AU - Buch, Stephan

AU - Stender, Stefan

AU - Noordam, Raymond

AU - Weng, Lu-Chen

AU - Weeke, Peter E

AU - Auer, Paul L

AU - Boehm, Bernhard

AU - Chen, Constance

AU - Choi, Hyon

AU - Curhan, Gary

AU - Denny, Joshua C

AU - De Vivo, Immaculata

AU - Eicher, John D

AU - Ellinghaus, David

AU - Folsom, Aaron R

AU - Fuchs, Charles

AU - Gala, Manish

AU - Haessler, Jeffrey

AU - Hofman, Albert

AU - Hu, Frank

AU - Hunter, David J

AU - Janssen, Harry L A

AU - Kang, Jae H

AU - Kooperberg, Charles

AU - Kraft, Peter

AU - Kratzer, Wolfgang

AU - Lieb, Wolfgang

AU - Lutsey, Pamela L

AU - Darwish Murad, Sarwa

AU - Nordestgaard, Børge G

AU - Pasquale, Louis R

AU - Reiner, Alex P

AU - Ridker, Paul M

AU - Rimm, Eric

AU - Rose, Lynda M

AU - Shaffer, Christian M

AU - Schafmayer, Clemens

AU - Tamimi, Rulla M

AU - Uitterlinden, Andre G

AU - Völker, Uwe

AU - Völzke, Henry

AU - Wakabayashi, Yoshiyuki

AU - Wiggs, Janey L.

AU - Zhu, Jun

AU - Roden, Dan M

AU - Stricker, Bruno H Ch

AU - Tang, Weihong

AU - Teumer, Alexander

AU - Hampe, Jochen

AU - Tybjærg-Hansen, Anne

AU - Chasman, Daniel I

AU - Chan, Andrew T

AU - Johnson, Andrew D

N1 - Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2016/8

Y1 - 2016/8

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1053/j.gastro.2016.04.007

DO - 10.1053/j.gastro.2016.04.007

M3 - Journal article

C2 - 27094239

VL - 151

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -