Journal Article

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

Oddsson, Asmundur, Masson, Gisli, Norddahl, Gudmundur L., Thorleifsson, Gudmar, Helgadottir, Anna, Sveinbjornsson, Gardar, Thorsteinsdottir, Unnur, Kristjansson, Ragnar P., Sverrisson, David A., Steingrimsdottir, Thora, Gunnarsson, Bjarni, Halldorsson, Gisli H., Olafsson, Isleifur, Rafnar, Thorunn, Bjornsson, Einar S., Holm, Hilma, Ferkingstad, Egil, Benonisdottir, Stefania, Gudbjartsson, Daniel F., Jensson, Brynjar O., Olafsson, Sigurdur, Stefansson, Kari, Sulem, Patrick, Deaton, Aimee M., Jonsdottir, Ingileif, Eyjolfsson, Gudmundur I., Arnadottir, Gudny A., Sigurdardottir, Olof, Zink, Florian, Jonsson, Stefan, Gretarsdottir, Solveig, Stefansson, Olafur A.

2018

Overview

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. Genome-wide association studies have so far identified eight risk loci for gallstone disease. Here, the authors perform meta-analysis in cohorts from Iceland and the UK which reveals further 21 common and low-frequency risk variants that highlight the role of bile acid homeostasis in gallstone disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/43 / 631/208/1516 / 631/208/205/2138 / 692/4020/1503/1328/1498/1376 / 692/4020/2741/44/1497 / alpha 1-Antitrypsin - genetics / Bile / Bile acids / Calculi / Cholecystectomy / Disease / Gallstones / Gallstones - genetics / Gallstones - metabolism / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Hepatocyte nuclear factor 4 / Hepatocyte Nuclear Factor 4 - genetics / Humanities and Social Sciences / Humans / Intestine / Loci / Low frequencies / Meta-analysis / multidisciplinary / Mutation, Missense - genetics / Organic Anion Transporters, Sodium-Dependent - genetics / Science / Science (multidisciplinary) / Sodium / Symporters - genetics