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

AD Joshi, C Andersson, S Buch, S Stender, Raymond Noordam, LC Weng, PE Weeke, PL Auer, B Boehm, C (Christopher Li Hsian) Chen, H Choi, G Curhan, JC Denny, I de Vivo, JD Eicher, D Ellinghaus, AR Folsom, C Fuchs, M Gala, J HaesslerBert Hofman, F Hu, DJ Hunter, HLA Janssen, JH Kang, C Kooperberg, P Kraft, W Kratzer, W Lieb, PL Lutsey, Sarwa Darwish Murad, BG Nordestgaard, LR Pasquale, AP Reiner, PM Ridker, E Rirnribi, LM Rose, CM Shaffer, C Schafmayer, RM Tamimi, André Uitterlinden, U Volker, H Volzke, Y Wakabayashi, JL Wiggs, J Zhu, DM Roden, Bruno Stricker, WH Tang, A Teumer, J Hampe, A Tybjmrg-Hansen, DI Chasman, T Andrew, D Andrew

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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 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.
Original languageUndefined/Unknown
Pages (from-to)351-+
Issue number2
Publication statusPublished - 2016

Research programs

  • EMC MM-01-39-09-A
  • EMC MM-04-20-01
  • EMC MM-04-20-02-A
  • EMC NIHES-01-64-01

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