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

Egil Ferkingstad, Asmundur Oddsson, Solveig Gretarsdottir, Stefania Benonisdottir, Gudmar Thorleifsson, Aimee M. Deaton, Stefan Jonsson, Olafur A. Stefansson, Gudmundur L. Norddahl, Florian Zink, Gudny A. Arnadottir, Bjarni Gunnarsson, Gisli H. Halldorsson, Anna Helgadottir, Brynjar O. Jensson, Ragnar P. Kristjansson, Gardar Sveinbjornsson, David A. Sverrisson, Gisli Masson, Isleifur Olafsson, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Hilma Holm, Ingileif Jonsdottir, Sigurdur Olafsson, Thora Steingrimsdottir, Thorunn Rafnar, Einar S. Bjornsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Patrick Sulem () and Kari Stefansson ()
Additional contact information
Egil Ferkingstad: deCODE Genetics/Amgen, Inc.
Asmundur Oddsson: deCODE Genetics/Amgen, Inc.
Solveig Gretarsdottir: deCODE Genetics/Amgen, Inc.
Stefania Benonisdottir: deCODE Genetics/Amgen, Inc.
Gudmar Thorleifsson: deCODE Genetics/Amgen, Inc.
Aimee M. Deaton: deCODE Genetics/Amgen, Inc.
Stefan Jonsson: deCODE Genetics/Amgen, Inc.
Olafur A. Stefansson: deCODE Genetics/Amgen, Inc.
Gudmundur L. Norddahl: deCODE Genetics/Amgen, Inc.
Florian Zink: deCODE Genetics/Amgen, Inc.
Gudny A. Arnadottir: deCODE Genetics/Amgen, Inc.
Bjarni Gunnarsson: deCODE Genetics/Amgen, Inc.
Gisli H. Halldorsson: deCODE Genetics/Amgen, Inc.
Anna Helgadottir: deCODE Genetics/Amgen, Inc.
Brynjar O. Jensson: deCODE Genetics/Amgen, Inc.
Ragnar P. Kristjansson: deCODE Genetics/Amgen, Inc.
Gardar Sveinbjornsson: deCODE Genetics/Amgen, Inc.
David A. Sverrisson: deCODE Genetics/Amgen, Inc.
Gisli Masson: deCODE Genetics/Amgen, Inc.
Isleifur Olafsson: Landspítali University Hospital
Gudmundur I. Eyjolfsson: Laboratory in Mjódd (RAM)
Olof Sigurdardottir: Akureyri Hospital
Hilma Holm: deCODE Genetics/Amgen, Inc.
Ingileif Jonsdottir: deCODE Genetics/Amgen, Inc.
Sigurdur Olafsson: Landspitali University Hospital
Thora Steingrimsdottir: University of Iceland
Thorunn Rafnar: deCODE Genetics/Amgen, Inc.
Einar S. Bjornsson: University of Iceland
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07460-y

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