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.
Highlights
Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy
Sequence variants at eight loci have been reported through genomewide association studies (GWAS) to affect the risk of gallstone disease, including missense variants in ABCG5/ABCG85, encoding ATP-binding cassette (ABC) transporters involved in the secretion of cholesterol into bile[6]
We find four novel low-frequency sequence variants in SLC10A2, SERPINA1 and HNF4A that associate with gallstone disease
Summary
Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. 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%). Sequence variants at eight loci have been reported through genomewide association studies (GWAS) to affect the risk of gallstone disease, including missense variants in ABCG5/ABCG85, encoding ATP-binding cassette (ABC) transporters involved in the secretion of cholesterol into bile[6]. To search for sequence variants affecting the risk of gallstone disease, we perform a genome-wide association study (GWAS) of 27,174 cases and 736,838 controls from Iceland and the UK biobank. With the discovery of gallstone-associated variants in SLC10A2, we highlight a role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility
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