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

Gastroenterology. 2016 Aug;151(2):351-363.e28. doi: 10.1053/j.gastro.2016.04.007. Epub 2016 Apr 16.

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.

Keywords: GWAS; Genetics; Risk Factors; SNP.

Publication types

  • Meta-Analysis

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / genetics*
  • Adult
  • African Americans / genetics
  • Aged
  • Case-Control Studies
  • Cholesterol / metabolism
  • European Continental Ancestry Group / genetics
  • Female
  • Gallstones / genetics*
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Hispanic Americans / genetics
  • Humans
  • Lipid Metabolism / genetics
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide

Substances

  • ABCG8 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • Cholesterol