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Nat Commun. 2018 Nov 30;9(1):5101. doi: 10.1038/s41467-018-07460-y.

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

Author information

1
deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.
2
Department of Clinical Biochemistry, Landspítali University Hospital, Reykjavik, 101, Iceland.
3
Laboratory in Mjódd (RAM), Reykjavik, 109, Iceland.
4
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, 600, Iceland.
5
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
6
Department of Immunology, Landspitali University Hospital, Reykjavik, 101, Iceland.
7
Department of Internal Medicine, Landspitali University Hospital, Reykjavik, 101, Iceland.
8
Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, 101, Iceland.
9
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland.
10
deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland. patrick.sulem@decode.is.
11
deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland. kstefans@decode.is.
12
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is.

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.

PMID:
30504769
PMCID:
PMC6269469
DOI:
10.1038/s41467-018-07460-y
[Indexed for MEDLINE]
Free PMC Article

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