A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Manuel A. Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A. Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, Sören Mucha, Mitja I. Kurki, Dalin Li, Mauro D'Amato, Vito Annese, Severine Vermeire, Rinse K. Weersma, Jonas Halfvarson, Paulina Paavola-Sakki, Maarit LappalainenMonkol Lek, Beryl Cummings, Taru Tukiainen, Talin Haritunians, Leena Halme, Lotta L.E. Koskinen, Ashwin N. Ananthakrishnan, Yang Luo, Graham A. Heap, Marijn C. Visschedijk, UK IBD Genetics Consortiumw, NIDDK IBD Genetics Consortium, Daniel G. MacArthur, Benjamin M. Neale, Tariq Ahmad, Carl A. Anderson, Steven R. Brant, Richard H. Duerr, Mark S. Silverberg, Judy H. Cho, Aarno Palotie, Päivi Saavalainen, Kimmo Kontula, Martti Färkkilä, Dermot P.B. McGovern, Andre Franke, Kari Stefansson, John D. Rioux, Ramnik J. Xavier, Mark J. Daly

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35 Citations (Scopus)


Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10 â '7, odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

Original languageEnglish
Article number12342
Number of pages8
JournalNature Communications
Publication statusPublished - 9 Aug 2016
Externally publishedYes

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