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Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

ABSTRACT: Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR?=?1.36 [1.25-1.49], P?=?2.1?×?10-12, MAF?=?1%; Val98Ile: OR?=?1.15 [1.10-1.20], P?=?1.8?×?10-10, MAF?=?4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.

SUBMITTER: Ferkingstad E

PROVIDER: S-EPMC6269469 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

Ferkingstad Egil E Oddsson Asmundur A Gretarsdottir Solveig S Benonisdottir Stefania S Thorleifsson Gudmar G Deaton Aimee M AM Jonsson Stefan S Stefansson Olafur A OA Norddahl Gudmundur L GL Zink Florian F Arnadottir Gudny A GA Gunnarsson Bjarni B Halldorsson Gisli H GH Helgadottir Anna A Jensson Brynjar O BO Kristjansson Ragnar P RP Sveinbjornsson Gardar G Sverrisson David A DA Masson Gisli G Olafsson Isleifur I Eyjolfsson Gudmundur I GI Sigurdardottir Olof O Holm Hilma H Jonsdottir Ingileif I Olafsson Sigurdur S Steingrimsdottir Thora T Rafnar Thorunn T Bjornsson Einar S ES Thorsteinsdottir Unnur U Gudbjartsson Daniel F DF Sulem Patrick P Stefansson Kari K

Nature communications 20181130 1

Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased r ...[more]

PMID: 30504769

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Project description:Background & aimsA 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.

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Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

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Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

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