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; Stefán Jónsson; Ólafur A. Stefánsson; Guðmundur L. Norðdahl; Florian Zink; Gudny Arnadottir; Bjarni Gunnarsson; Gisli Halldorsson; Anna Helgadottir; Brynjar Örn Jensson; Ragnar P. Kristjánsson; Gardar Sveinbjornsson; Davíð A. Sverrisson; Gísli Másson; Isleifur Olafsson; Guðmundur I. Eyjólfsson; Ólöf Sigurðardóttir; Hilma Holm; Ingileif Jonsdottir; Sigurður Ólafsson; Thora Steingrimsdottir; Thorunn Rafnar; Einar Stefán Björnsson; Unnur Thorsteinsdottir; Daniel Gudbjartsson; patrick sulem; Kari Stefansson; Gudmundur L Norddahl; David A Sverrisson; Gudmundur I Eyjolfsson; Olof Sigurdardottir; Sigurdur Olafsson; Einar S Bjornsson

doi:10.1038/s41467-018-07460-y

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, Stefán Jónsson, Ólafur A. Stefánsson, Guðmundur L. Norðdahl, Florian Zink, Gudny Arnadottir, Bjarni Gunnarsson, Gisli Halldorsson, Anna Helgadottir, Brynjar Örn Jensson, Ragnar P. Kristjánsson, Gardar Sveinbjornsson, Davíð A. Sverrisson, Gísli Másson, Isleifur OlafssonGuðmundur I. Eyjólfsson, Ólöf Sigurðardóttir, Hilma Holm, Ingileif Jonsdottir, Sigurður Ólafsson, Thora Steingrimsdottir, Thorunn Rafnar, Einar Stefán Björnsson, Unnur Thorsteinsdottir, Daniel Gudbjartsson, patrick sulem, Kari Stefansson, Gudmundur L Norddahl, David A Sverrisson, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Sigurdur Olafsson, Einar S Bjornsson

University of Iceland, Iceland, Landspitali - The National University Hospital of Iceland

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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 genomewide 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.

Original language	English
Number of pages	5101
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07460-y
Publication status	Published - 30 Nov 2018

Other keywords

Cholelithiasis
Gall bladder
Genome-wide association studies
Medical genetics
Gallsteinar
Gallblaðra
Erfðafræði
Rannsóknir
læknisfr
Gen
Gallstones
Genome-Wide Association Study

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10.1038/s41467-018-07460-y

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Ferkingstad, E., Oddsson, A., Gretarsdottir, S., Benonisdottir, S., Thorleifsson, G., Deaton, A. M., Jónsson, S., Stefánsson, Ó. A., Norðdahl, G. L., Zink, F., Arnadottir, G., Gunnarsson, B., Halldorsson, G., Helgadottir, A., Jensson, B. Ö., Kristjánsson, R. P., Sveinbjornsson, G., Sverrisson, D. A., Másson, G., ... Bjornsson, E. S. (2018). Genome-wide association meta-analysis yields 20 loci associated with gallstone disease. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-07460-y

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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 genomewide 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.",

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author = "Egil Ferkingstad and Asmundur Oddsson and Solveig Gretarsdottir and Stefania Benonisdottir and Gudmar Thorleifsson and Deaton, {Aimee M.} and Stef{\'a}n J{\'o}nsson and Stef{\'a}nsson, {{\'O}lafur A.} and Nor{\dh}dahl, {Gu{\dh}mundur L.} and Florian Zink and Gudny Arnadottir and Bjarni Gunnarsson and Gisli Halldorsson and Anna Helgadottir and Jensson, {Brynjar {\"O}rn} and Kristj{\'a}nsson, {Ragnar P.} and Gardar Sveinbjornsson and Sverrisson, {Dav{\'i}{\dh} A.} and G{\'i}sli M{\'a}sson and Isleifur Olafsson and Eyj{\'o}lfsson, {Gu{\dh}mundur I.} and {\'O}l{\"o}f Sigur{\dh}ard{\'o}ttir and Hilma Holm and Ingileif Jonsdottir and Sigur{\dh}ur {\'O}lafsson and Thora Steingrimsdottir and Thorunn Rafnar and Bj{\"o}rnsson, {Einar Stef{\'a}n} and Unnur Thorsteinsdottir and Daniel Gudbjartsson and patrick sulem and Kari Stefansson and Norddahl, {Gudmundur L} and Sverrisson, {David A} and Eyjolfsson, {Gudmundur I} and Olof Sigurdardottir and Sigurdur Olafsson and Bjornsson, {Einar S}",

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Ferkingstad, E, Oddsson, A, Gretarsdottir, S, Benonisdottir, S, Thorleifsson, G, Deaton, AM, Jónsson, S, Stefánsson, ÓA, Norðdahl, GL, Zink, F, Arnadottir, G, Gunnarsson, B, Halldorsson, G, Helgadottir, A, Jensson, BÖ, Kristjánsson, RP, Sveinbjornsson, G, Sverrisson, DA, Másson, G, Olafsson, I, Eyjólfsson, GI, Sigurðardóttir, Ó, Holm, H, Jonsdottir, I , Ólafsson, S , Steingrimsdottir, T, Rafnar, T, Björnsson, ES , Thorsteinsdottir, U, Gudbjartsson, D, sulem, P, Stefansson, K, Norddahl, GL, Sverrisson, DA, Eyjolfsson, GI, Sigurdardottir, O, Olafsson, S & Bjornsson, ES 2018, 'Genome-wide association meta-analysis yields 20 loci associated with gallstone disease', Nature Communications, vol. 9, no. 1. https://doi.org/10.1038/s41467-018-07460-y

TY - JOUR

T1 - Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

AU - Ferkingstad, Egil

AU - Oddsson, Asmundur

AU - Gretarsdottir, Solveig

AU - Benonisdottir, Stefania

AU - Thorleifsson, Gudmar

AU - Deaton, Aimee M.

AU - Jónsson, Stefán

AU - Stefánsson, Ólafur A.

AU - Norðdahl, Guðmundur L.

AU - Zink, Florian

AU - Arnadottir, Gudny

AU - Gunnarsson, Bjarni

AU - Halldorsson, Gisli

AU - Helgadottir, Anna

AU - Jensson, Brynjar Örn

AU - Kristjánsson, Ragnar P.

AU - Sveinbjornsson, Gardar

AU - Sverrisson, Davíð A.

AU - Másson, Gísli

AU - Olafsson, Isleifur

AU - Eyjólfsson, Guðmundur I.

AU - Sigurðardóttir, Ólöf

AU - Holm, Hilma

AU - Jonsdottir, Ingileif

AU - Ólafsson, Sigurður

AU - Steingrimsdottir, Thora

AU - Rafnar, Thorunn

AU - Björnsson, Einar Stefán

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel

AU - sulem, patrick

AU - Stefansson, Kari

AU - Norddahl, Gudmundur L

AU - Sverrisson, David A

AU - Eyjolfsson, Gudmundur I

AU - Sigurdardottir, Olof

AU - Olafsson, Sigurdur

AU - Bjornsson, Einar S

PY - 2018/11/30

Y1 - 2018/11/30

N2 - 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 genomewide 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.

AB - 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 genomewide 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.

KW - Cholelithiasis

KW - Gall bladder

KW - Genome-wide association studies

KW - Medical genetics

KW - Gallsteinar

KW - Gallblaðra

KW - Erfðafræði

KW - Rannsóknir

KW - læknisfr

KW - Gen

KW - Gallstones

KW - Genome-Wide Association Study

KW - Cholelithiasis

KW - Gall bladder

KW - Genome-wide association studies

KW - Medical genetics

KW - Gallsteinar

KW - Gallblaðra

KW - Erfðafræði

KW - Rannsóknir

KW - læknisfr

KW - Gen

KW - Gallstones

KW - Genome-Wide Association Study

U2 - 10.1038/s41467-018-07460-y

DO - 10.1038/s41467-018-07460-y

M3 - Article

C2 - 30504769

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

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