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 journalArticle

139 Scopus citations

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; pcombined = 2.1 × 10-8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (prepl <0.05). FUT2 at chromosome 19q13 (rs602662; pcomb = 1.9 × 10-6, rs281377; pcomb = 2.1 × 10-6 and rs601338; pcomb = 2.7 × 10 -6) is notable due 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.

Original languageEnglish (US)
Pages (from-to)366-375
Number of pages10
JournalJournal of hepatology
Volume57
Issue number2
DOIs
StatePublished - Aug 1 2012

Keywords

  • Genome-wide association study
  • Immunogenetics
  • Primary sclerosing cholangitis
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Hepatology

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    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