Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
Joshi AD., Andersson C., Buch S., Stender S., Noordam R., Weng L-C., Weeke PE., Auer PL., Boehm B., Chen C., Choi H., Curhan G., Denny JC., De Vivo I., Eicher JD., Ellinghaus D., Folsom AR., Fuchs C., Gala M., Haessler J., Hofman A., Hu F., Hunter DJ., Janssen HLA., Kang JH., Kooperberg C., Kraft P., Kratzer W., Lieb W., Lutsey PL., Darwish Murad S., Nordestgaard BG., Pasquale LR., Reiner AP., Ridker PM., Rimm E., Rose LM., Shaffer CM., Schafmayer C., Tamimi RM., Uitterlinden AG., Völker U., Völzke H., Wakabayashi Y., Wiggs JL., Zhu J., Roden DM., Stricker BH., Tang W., Teumer A., Hampe J., Tybjærg-Hansen A., Chasman DI., Chan AT., Johnson AD.
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.