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

AD Joshi; C Andersson; S Buch; S Stender; Raymond Noordam; LC Weng; PE Weeke; PL Auer; B Boehm; C (Christopher Li Hsian) Chen; H Choi; G Curhan; JC Denny; I de Vivo; JD Eicher; D Ellinghaus; AR Folsom; C Fuchs; M Gala; J Haessler; Bert Hofman; F Hu; DJ Hunter; HLA Janssen; JH Kang; C Kooperberg; P Kraft; W Kratzer; W Lieb; PL Lutsey; Sarwa Darwish Murad; BG Nordestgaard; LR Pasquale; AP Reiner; PM Ridker; E Rirnribi; LM Rose; CM Shaffer; C Schafmayer; RM Tamimi; André Uitterlinden; U Volker; H Volzke; Y Wakabayashi; JL Wiggs; J Zhu; DM Roden; Bruno Stricker; WH Tang; A Teumer; J Hampe; A Tybjmrg-Hansen; DI Chasman; T Andrew; D Andrew

doi:10.1053/j.gastro.2016.04.007

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

AD Joshi, C Andersson, S Buch, S Stender, Raymond Noordam, LC Weng, PE Weeke, PL Auer, B Boehm, C (Christopher Li Hsian) Chen, H Choi, G Curhan, JC Denny, I de Vivo, JD Eicher, D Ellinghaus, AR Folsom, C Fuchs, M Gala, J HaesslerBert Hofman, F Hu, DJ Hunter, HLA Janssen, JH Kang, C Kooperberg, P Kraft, W Kratzer, W Lieb, PL Lutsey, Sarwa Darwish Murad, BG Nordestgaard, LR Pasquale, AP Reiner, PM Ridker, E Rirnribi, LM Rose, CM Shaffer, C Schafmayer, RM Tamimi, André Uitterlinden, U Volker, H Volzke, Y Wakabayashi, JL Wiggs, J Zhu, DM Roden, Bruno Stricker, WH Tang, A Teumer, J Hampe, A Tybjmrg-Hansen, DI Chasman, T Andrew, D Andrew

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

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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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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	Undefined/Unknown
Pages (from-to)	351-+
Journal	Gastroenterology
Volume	151
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2016.04.007
Publication status	Published - 2016

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10.1053/j.gastro.2016.04.007

http://hdl.handle.net/1765/96260

Cite this

Joshi, AD., Andersson, C., Buch, S., Stender, S., Noordam, R., Weng, LC., 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., ... Andrew, D. (2016). Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies. Gastroenterology, 151(2), 351-+. https://doi.org/10.1053/j.gastro.2016.04.007

@article{2fb5f0b143664f449dfd8412c3dec61f,

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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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.",

author = "AD Joshi and C Andersson and S Buch and S Stender and Raymond Noordam and LC Weng and PE Weeke and PL Auer and B Boehm and Chen, {C (Christopher Li Hsian)} and H Choi and G Curhan and JC Denny and {de Vivo}, I and JD Eicher and D Ellinghaus and AR Folsom and C Fuchs and M Gala and J Haessler and Bert Hofman and F Hu and DJ Hunter and HLA Janssen and JH Kang and C Kooperberg and P Kraft and W Kratzer and W Lieb and PL Lutsey and {Darwish Murad}, Sarwa and BG Nordestgaard and LR Pasquale and AP Reiner and PM Ridker and E Rirnribi and LM Rose and CM Shaffer and C Schafmayer and RM Tamimi and Andr{\'e} Uitterlinden and U Volker and H Volzke and Y Wakabayashi and JL Wiggs and J Zhu and DM Roden and Bruno Stricker and WH Tang and A Teumer and J Hampe and A Tybjmrg-Hansen and DI Chasman and T Andrew and D Andrew",

year = "2016",

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

language = "Undefined/Unknown",

volume = "151",

pages = "351--+",

journal = "Gastroenterology",

issn = "0016-5085",

number = "2",

}

Joshi, AD, Andersson, C, Buch, S, Stender, S, Noordam, R, Weng, LC, 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, B, 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, Rirnribi, E, Rose, LM, Shaffer, CM, Schafmayer, C, Tamimi, RM, Uitterlinden, A, Volker, U, Volzke, H, Wakabayashi, Y, Wiggs, JL, Zhu, J, Roden, DM, Stricker, B, Tang, WH, Teumer, A, Hampe, J, Tybjmrg-Hansen, A, Chasman, DI, Andrew, T & Andrew, D 2016, 'Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies', Gastroenterology, vol. 151, no. 2, pp. 351-+. https://doi.org/10.1053/j.gastro.2016.04.007

TY - JOUR

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

AU - Joshi, AD

AU - Andersson, C

AU - Buch, S

AU - Stender, S

AU - Noordam, Raymond

AU - Weng, LC

AU - Weeke, PE

AU - Auer, PL

AU - Boehm, B

AU - Chen, C (Christopher Li Hsian)

AU - Choi, H

AU - Curhan, G

AU - Denny, JC

AU - de Vivo, I

AU - Eicher, JD

AU - Ellinghaus, D

AU - Folsom, AR

AU - Fuchs, C

AU - Gala, M

AU - Haessler, J

AU - Hofman, Bert

AU - Hu, F

AU - Hunter, DJ

AU - Janssen, HLA

AU - Kang, JH

AU - Kooperberg, C

AU - Kraft, P

AU - Kratzer, W

AU - Lieb, W

AU - Lutsey, PL

AU - Darwish Murad, Sarwa

AU - Nordestgaard, BG

AU - Pasquale, LR

AU - Reiner, AP

AU - Ridker, PM

AU - Rirnribi, E

AU - Rose, LM

AU - Shaffer, CM

AU - Schafmayer, C

AU - Tamimi, RM

AU - Uitterlinden, André

AU - Volker, U

AU - Volzke, H

AU - Wakabayashi, Y

AU - Wiggs, JL

AU - Zhu, J

AU - Roden, DM

AU - Stricker, Bruno

AU - Tang, WH

AU - Teumer, A

AU - Hampe, J

AU - Tybjmrg-Hansen, A

AU - Chasman, DI

AU - Andrew, T

AU - Andrew, D

PY - 2016

Y1 - 2016

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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 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 x 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 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 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 x 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.

U2 - 10.1053/j.gastro.2016.04.007

DO - 10.1053/j.gastro.2016.04.007

M3 - Article

SN - 0016-5085

VL - 151

SP - 351-+

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -