Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

Trine Folseraas; Espen Melum; Philipp Rausch; Brian D. Juran; Eva Ellinghaus; Alexey Shiryaev; Jon K. Laerdahl; David Ellinghaus; Christoph Schramm; Tobias J. Weismüller; Daniel Nils Gotthardt; Johannes Roksund Hov; Ole Petter Clausen; Rinse K. Weersma; Marcel Janse; Kirsten Muri Boberg; Einar Björnsson; Hanns-Ulrich Marschall; Isabelle Cleynen; Philip Rosenstiel; Kristian Holm; Andreas Teufel; Christian Rust; Christian Gieger; H.-Erich Wichmann; Annika Bergquist; Euijung Ryu; Cyriel Y. Ponsioen; Heiko Runz; Martina Sterneck; Severine Vermeire; Ulrich Beuers; Cisca Wijmenga; Erik Schrumpf; Michael P. Manns; Konstantinos N. Lazaridis; Stefan Schreiber; John F. Baines; Andre Franke; Tom H. Karlsen

doi:https://doi.org/10.1016/j.jhep.2012.03.031

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

Trine Folseraas, Espen Melum, Philipp Rausch, Brian D. Juran, Eva Ellinghaus, Alexey Shiryaev, Jon K. Laerdahl, David Ellinghaus, Christoph Schramm, Tobias J. Weismüller, Daniel Nils Gotthardt, Johannes Roksund Hov, Ole Petter Clausen, Rinse K. Weersma, Marcel Janse, Kirsten Muri Boberg, Einar Björnsson, Hanns-Ulrich Marschall, Isabelle Cleynen, Philip RosenstielKristian Holm, Andreas Teufel, Christian Rust, Christian Gieger, H.-Erich Wichmann, Annika Bergquist, Euijung Ryu, Cyriel Y. Ponsioen, Heiko Runz, Martina Sterneck, Severine Vermeire, Ulrich Beuers, Cisca Wijmenga, Erik Schrumpf, Michael P. Manns, Konstantinos N. Lazaridis, Stefan Schreiber, John F. Baines, Andre Franke, Tom H. Karlsen

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

188 Citations (Scopus)

Abstract

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Original language	English
Pages (from-to)	366-375
Journal	Journal of Hepatology
Volume	57
Issue number	2
DOIs	https://doi.org/10.1016/j.jhep.2012.03.031
Publication status	Published - 2012

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https://doi.org/10.1016/j.jhep.2012.03.031

Cite this

Folseraas, T., Melum, E., Rausch, P., Juran, B. D., Ellinghaus, E., Shiryaev, A., Laerdahl, J. K., Ellinghaus, D., Schramm, C., Weismüller, T. J., Gotthardt, D. N., Hov, J. R., Clausen, O. P., Weersma, R. K., Janse, M., Boberg, K. M., Björnsson, E., Marschall, H.-U., Cleynen, I., ... Karlsen, T. H. (2012). Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. Journal of Hepatology, 57(2), 366-375. https://doi.org/10.1016/j.jhep.2012.03.031

@article{da816b9641d140f69ea5316accae6b81,

title = "Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci",

abstract = "Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved",

author = "Trine Folseraas and Espen Melum and Philipp Rausch and Juran, {Brian D.} and Eva Ellinghaus and Alexey Shiryaev and Laerdahl, {Jon K.} and David Ellinghaus and Christoph Schramm and Weism{\"u}ller, {Tobias J.} and Gotthardt, {Daniel Nils} and Hov, {Johannes Roksund} and Clausen, {Ole Petter} and Weersma, {Rinse K.} and Marcel Janse and Boberg, {Kirsten Muri} and Einar Bj{\"o}rnsson and Hanns-Ulrich Marschall and Isabelle Cleynen and Philip Rosenstiel and Kristian Holm and Andreas Teufel and Christian Rust and Christian Gieger and H.-Erich Wichmann and Annika Bergquist and Euijung Ryu and Ponsioen, {Cyriel Y.} and Heiko Runz and Martina Sterneck and Severine Vermeire and Ulrich Beuers and Cisca Wijmenga and Erik Schrumpf and Manns, {Michael P.} and Lazaridis, {Konstantinos N.} and Stefan Schreiber and Baines, {John F.} and Andre Franke and Karlsen, {Tom H.}",

year = "2012",

doi = "https://doi.org/10.1016/j.jhep.2012.03.031",

language = "English",

volume = "57",

pages = "366--375",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "2",

}

Folseraas, T, Melum, E, Rausch, P, Juran, BD, Ellinghaus, E, Shiryaev, A, Laerdahl, JK, Ellinghaus, D, Schramm, C, Weismüller, TJ, Gotthardt, DN, Hov, JR, Clausen, OP, Weersma, RK, Janse, M, Boberg, KM, Björnsson, E, Marschall, H-U, Cleynen, I, Rosenstiel, P, Holm, K, Teufel, A, Rust, C, Gieger, C, Wichmann, H-E, Bergquist, A, Ryu, E, Ponsioen, CY, Runz, H, Sterneck, M, Vermeire, S, Beuers, U, Wijmenga, C, Schrumpf, E, Manns, MP, Lazaridis, KN, Schreiber, S, Baines, JF, Franke, A & Karlsen, TH 2012, 'Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci', Journal of Hepatology, vol. 57, no. 2, pp. 366-375. https://doi.org/10.1016/j.jhep.2012.03.031

TY - JOUR

T1 - Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

AU - Folseraas, Trine

AU - Melum, Espen

AU - Rausch, Philipp

AU - Juran, Brian D.

AU - Ellinghaus, Eva

AU - Shiryaev, Alexey

AU - Laerdahl, Jon K.

AU - Ellinghaus, David

AU - Schramm, Christoph

AU - Weismüller, Tobias J.

AU - Gotthardt, Daniel Nils

AU - Hov, Johannes Roksund

AU - Clausen, Ole Petter

AU - Weersma, Rinse K.

AU - Janse, Marcel

AU - Boberg, Kirsten Muri

AU - Björnsson, Einar

AU - Marschall, Hanns-Ulrich

AU - Cleynen, Isabelle

AU - Rosenstiel, Philip

AU - Holm, Kristian

AU - Teufel, Andreas

AU - Rust, Christian

AU - Gieger, Christian

AU - Wichmann, H.-Erich

AU - Bergquist, Annika

AU - Ryu, Euijung

AU - Ponsioen, Cyriel Y.

AU - Runz, Heiko

AU - Sterneck, Martina

AU - Vermeire, Severine

AU - Beuers, Ulrich

AU - Wijmenga, Cisca

AU - Schrumpf, Erik

AU - Manns, Michael P.

AU - Lazaridis, Konstantinos N.

AU - Schreiber, Stefan

AU - Baines, John F.

AU - Franke, Andre

AU - Karlsen, Tom H.

PY - 2012

Y1 - 2012

N2 - Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

AB - Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

U2 - https://doi.org/10.1016/j.jhep.2012.03.031

DO - https://doi.org/10.1016/j.jhep.2012.03.031

M3 - Article

C2 - 22521342

SN - 0168-8278

VL - 57

SP - 366

EP - 375

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -