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A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease


With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries1,2. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value PCCA = 4.1 × 10−9), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 × 10−7) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8–2.6, P = 1.4 × 10−14) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.

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Figure 1: Overview of the physical and genetic structure of the ABCG5/ABCG8 region.


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The cooperation of all patients, their families and physicians is gratefully acknowledged. The authors gratefully acknowledge the support by the following heads of surgical departments: I. Vogel (Städtisches Krankenhaus Kiel), H. Dittrich (Rendsburg), J. Belz (Husum), R. Quäschling (Eckernförde), H. Shekarriz (Schleswig), V. Mendel (Flensburg), W. Neugebauer (Flensburg), F. Kallinowski (Heide), J. Klima (Niebüll), M. Sailer (Hamburg) and A. Schafmayer (Lüneburg). Special thanks are given to C. Fürstenau, T. Wesse, B. Petersen, L. Bossen, T. Henke, S. Ehlers, A. Dietsch and V. Pucken for technical assistance. This study was supported by the German Ministry of Education and Research through the POPGEN biobank project (01GS0426, 01GR0468), the MediGrid project and the National Genotyping Platforms in Kiel and Cologne and by the German Research Council (Ha 3091/2-1, 4-1, La 997/3-1), Applied Biosystems, Mucosaimmunologie gGmbH and the Medical Faculty Kiel. The SHIP recruitment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The Chilean study was supported by grants from FONDECYT (Fondo Nacional de Desarrollo Científico y Tecnologógico) (numbers 1040820 (to J.F.M.) and 1030744 (to F.N.)).

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Authors and Affiliations



S.B. performed the SNP selection, genotyping and data analysis and prepared the figures and tables; C.S. coordinated the Kiel recruitment, phenotyped patients and helped write the paper; J.E., H.v.E., C.H., B.T. and M.S. recruited patients and helped write the paper. C.B., I.B., C.K. and P.N. performed the chip genotyping and chip data analysis; H.V. and D.R. coordinated the SHIP recruitment and participated in experimental design; J.F.M., F.N. coordinated the recruitment in Chile and participated in experimental design; A.F., M.B., A.E., T.L. and M.W. helped with data analysis and genotyping and F.L., F.F., U.R.F., S.S., P.N. and J.T. helped design the experiment, supported recruitment and helped write the paper. M.K. supervised and performed the statistical analysis and edited the paper. J.H. designed and supervised the experiment, performed data analysis and wrote the manuscript. All authors have revised the manuscript for intellectual content.

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Correspondence to Jochen Hampe.

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The authors declare no competing financial interests.

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Supplementary Figures 1–2, Supplementary Tables 1–2, Supplementary Methods, Supplementary Note (PDF 205 kb)

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Buch, S., Schafmayer, C., Völzke, H. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 39, 995–999 (2007).

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