Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

Amit D Joshi; Charlotte Andersson; Stephan Buch; Stefan Stender; Raymond Noordam; Lu-Chen Weng; Peter E Weeke; Paul L Auer; Bernhard Boehm; Constance Chen; Hyon Choi; Gary Curhan; Joshua C Denny; Immaculata De Vivo; John D Eicher; David Ellinghaus; Aaron R Folsom; Charles Fuchs; Manish Gala; Jeffrey Haessler; Albert Hofman; Frank Hu; David J Hunter; Harry L A Janssen; Jae H Kang; Charles Kooperberg; Peter Kraft; Wolfgang Kratzer; Wolfgang Lieb; Pamela L Lutsey; Sarwa Darwish Murad; Børge G Nordestgaard; Louis R Pasquale; Alex P Reiner; Paul M Ridker; Eric Rimm; Lynda M Rose; Christian M Shaffer; Clemens Schafmayer; Rulla M Tamimi; Andre G Uitterlinden; Uwe Völker; Henry Völzke; Yoshiyuki Wakabayashi; Janey L. Wiggs; Jun Zhu; Dan M Roden; Bruno H Ch Stricker; Weihong Tang; Alexander Teumer; Jochen Hampe; Anne Tybjærg-Hansen; Daniel I Chasman; Andrew T Chan; Andrew D Johnson

doi:10.1053/j.gastro.2016.04.007

Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

Amit D Joshi, Charlotte Andersson, Stephan Buch, Stefan Stender, Raymond Noordam, Lu-Chen Weng, Peter E Weeke, Paul L Auer, Bernhard Boehm, Constance Chen, Hyon Choi, Gary Curhan, Joshua C Denny, Immaculata De Vivo, John D Eicher, David Ellinghaus, Aaron R Folsom, Charles Fuchs, Manish Gala, Jeffrey HaesslerAlbert Hofman, Frank Hu, David J Hunter, Harry L A Janssen, Jae H Kang, Charles Kooperberg, Peter Kraft, Wolfgang Kratzer, Wolfgang Lieb, Pamela L Lutsey, Sarwa Darwish Murad, Børge G Nordestgaard, Louis R Pasquale, Alex P Reiner, Paul M Ridker, Eric Rimm, Lynda M Rose, Christian M Shaffer, Clemens Schafmayer, Rulla M Tamimi, Andre G Uitterlinden, Uwe Völker, Henry Völzke, Yoshiyuki Wakabayashi, Janey L. Wiggs, Jun Zhu, Dan M Roden, Bruno H Ch Stricker, Weihong Tang, Alexander Teumer, Jochen Hampe, Anne Tybjærg-Hansen, Daniel I Chasman, Andrew T Chan, Andrew D Johnson

Department of Clinical Medicine

40 Citations (Scopus)

Abstract

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.

METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.

RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.

CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

Original language	English
Journal	Gastroenterology
Volume	151
Issue number	2
Number of pages	351
ISSN	0016-5085
DOIs	https://doi.org/10.1053/j.gastro.2016.04.007
Publication status	Published - 1 Aug 2016

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10.1053/j.gastro.2016.04.007

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Joshi, A. D., Andersson, C., Buch, S., Stender, S., Noordam, R., Weng, L.-C., Weeke, P. E., Auer, P. L., Boehm, B., Chen, C., Choi, H., Curhan, G., Denny, J. C., De Vivo, I., Eicher, J. D., Ellinghaus, D., Folsom, A. R., Fuchs, C., Gala, M., ... Johnson, A. D. (2016). Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies. Gastroenterology, 151(2). https://doi.org/10.1053/j.gastro.2016.04.007

Joshi, AD, Andersson, C, Buch, S, Stender, S, Noordam, R, Weng, L-C, Weeke, PE, Auer, PL, Boehm, B, Chen, C, Choi, H, Curhan, G, Denny, JC, De Vivo, I, Eicher, JD, Ellinghaus, D, Folsom, AR, Fuchs, C, Gala, M, Haessler, J, Hofman, A, Hu, F, Hunter, DJ, Janssen, HLA, Kang, JH, Kooperberg, C, Kraft, P, Kratzer, W, Lieb, W, Lutsey, PL, Darwish Murad, S, Nordestgaard, BG, Pasquale, LR, Reiner, AP, Ridker, PM, Rimm, E, Rose, LM, Shaffer, CM, Schafmayer, C, Tamimi, RM, Uitterlinden, AG, Völker, U, Völzke, H, Wakabayashi, Y, Wiggs, JL, Zhu, J, Roden, DM, Stricker, BHC, Tang, W, Teumer, A, Hampe, J, Tybjærg-Hansen, A, Chasman, DI, Chan, AT & Johnson, AD 2016, 'Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies', Gastroenterology, vol. 151, no. 2. https://doi.org/10.1053/j.gastro.2016.04.007

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title = "Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies",

abstract = "BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.",

keywords = "Journal Article",

author = "Joshi, {Amit D} and Charlotte Andersson and Stephan Buch and Stefan Stender and Raymond Noordam and Lu-Chen Weng and Weeke, {Peter E} and Auer, {Paul L} and Bernhard Boehm and Constance Chen and Hyon Choi and Gary Curhan and Denny, {Joshua C} and {De Vivo}, Immaculata and Eicher, {John D} and David Ellinghaus and Folsom, {Aaron R} and Charles Fuchs and Manish Gala and Jeffrey Haessler and Albert Hofman and Frank Hu and Hunter, {David J} and Janssen, {Harry L A} and Kang, {Jae H} and Charles Kooperberg and Peter Kraft and Wolfgang Kratzer and Wolfgang Lieb and Lutsey, {Pamela L} and {Darwish Murad}, Sarwa and Nordestgaard, {B{\o}rge G} and Pasquale, {Louis R} and Reiner, {Alex P} and Ridker, {Paul M} and Eric Rimm and Rose, {Lynda M} and Shaffer, {Christian M} and Clemens Schafmayer and Tamimi, {Rulla M} and Uitterlinden, {Andre G} and Uwe V{\"o}lker and Henry V{\"o}lzke and Yoshiyuki Wakabayashi and Wiggs, {Janey L.} and Jun Zhu and Roden, {Dan M} and Stricker, {Bruno H Ch} and Weihong Tang and Alexander Teumer and Jochen Hampe and Anne Tybj{\ae}rg-Hansen and Chasman, {Daniel I} and Chan, {Andrew T} and Johnson, {Andrew D}",

year = "2016",

month = aug,

day = "1",

doi = "10.1053/j.gastro.2016.04.007",

language = "English",

volume = "151",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier",

number = "2",

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TY - JOUR

T1 - Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

AU - Joshi, Amit D

AU - Andersson, Charlotte

AU - Buch, Stephan

AU - Stender, Stefan

AU - Noordam, Raymond

AU - Weng, Lu-Chen

AU - Weeke, Peter E

AU - Auer, Paul L

AU - Boehm, Bernhard

AU - Chen, Constance

AU - Choi, Hyon

AU - Curhan, Gary

AU - Denny, Joshua C

AU - De Vivo, Immaculata

AU - Eicher, John D

AU - Ellinghaus, David

AU - Folsom, Aaron R

AU - Fuchs, Charles

AU - Gala, Manish

AU - Haessler, Jeffrey

AU - Hofman, Albert

AU - Hu, Frank

AU - Hunter, David J

AU - Janssen, Harry L A

AU - Kang, Jae H

AU - Kooperberg, Charles

AU - Kraft, Peter

AU - Kratzer, Wolfgang

AU - Lieb, Wolfgang

AU - Lutsey, Pamela L

AU - Darwish Murad, Sarwa

AU - Nordestgaard, Børge G

AU - Pasquale, Louis R

AU - Reiner, Alex P

AU - Ridker, Paul M

AU - Rimm, Eric

AU - Rose, Lynda M

AU - Shaffer, Christian M

AU - Schafmayer, Clemens

AU - Tamimi, Rulla M

AU - Uitterlinden, Andre G

AU - Völker, Uwe

AU - Völzke, Henry

AU - Wakabayashi, Yoshiyuki

AU - Wiggs, Janey L.

AU - Zhu, Jun

AU - Roden, Dan M

AU - Stricker, Bruno H Ch

AU - Tang, Weihong

AU - Teumer, Alexander

AU - Hampe, Jochen

AU - Tybjærg-Hansen, Anne

AU - Chasman, Daniel I

AU - Chan, Andrew T

AU - Johnson, Andrew D

PY - 2016/8/1

Y1 - 2016/8/1

N2 - BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

AB - BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease.METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls.RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse.CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

KW - Journal Article

U2 - 10.1053/j.gastro.2016.04.007

DO - 10.1053/j.gastro.2016.04.007

M3 - Journal article

C2 - 27094239

SN - 0016-5085

VL - 151

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

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