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

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http://hdl.handle.net/10138/167006

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Rivas , M A , Graham , D , Sulem , P , Stevens , C , Desch , A N , Goyette , P , Gudbjartsson , D , Jonsdottir , I , Thorsteinsdottir , U , Degenhardt , F , Mucha , S , Kurki , M I , Li , D , D'Amato , M , Annese , V , Vermeire , S , Weersma , R K , Halfvarson , J , Paavola-Sakki , A L P , Lappalainen , A M , Lek , M , Cummings , B , Tukiainen , T , Haritunians , T , Halme , L , Koskinen , L L E , Ananthakrishnan , A N , Luo , Y , Heap , G A , Visschedijk , M C , MacArthur , D G , Neale , B M , Ahmad , T , Anderson , C A , Brant , S R , Duerr , R H , Silverberg , M S , Cho , J H , Palotie , A , Saavalainen , P , Kontula , K , Farkkila , M , McGovern , D P B , Franke , A , Stefansson , K , Rioux , J D , Xavier , R J & Daly , M J 2016 , ' A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis ' , Nature Communications , vol. 7 , 12342 . https://doi.org/10.1038/ncomms12342

Title: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Author: Rivas, Manuel A.; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A. Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; Mucha, Soeren; Kurki, Mitja I.; Li, Dalin; D'Amato, Mauro; Annese, Vito; Vermeire, Severine; Weersma, Rinse K.; Halfvarson, Jonas; Paavola-Sakki, Anu Liisa Paulina; Lappalainen, Anne Maarit; Lek, Monkol; Cummings, Beryl; Tukiainen, Taru; Haritunians, Talin; Halme, Leena; Koskinen, Lotta L. E.; Ananthakrishnan, Ashwin N.; Luo, Yang; Heap, Graham A.; Visschedijk, Marijn C.; MacArthur, Daniel G.; Neale, Benjamin M.; Ahmad, Tariq; Anderson, Carl A.; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H.; Palotie, Aarno; Saavalainen, Paivi; Kontula, Kimmo; Farkkila, Martti; McGovern, Dermot P. B.; Franke, Andre; Stefansson, Kari; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.
Contributor: University of Helsinki, Department of Medicine
University of Helsinki, Clinicum
University of Helsinki, Broad Inst Harvard, Broad Institute, Massachusetts Institute of Technology (MIT), Harvard University
University of Helsinki, II kirurgian klinikka
University of Helsinki, Research Programs Unit
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2016-08
Language: eng
Number of pages: 7
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/167006
Abstract: 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 x 10(-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.
Subject: INFLAMMATORY-BOWEL-DISEASE
OF-FUNCTION VARIANTS
SUSCEPTIBILITY LOCI
RARE VARIANTS
RISK
ASSOCIATION
NUMBER
POPULATION
IMPUTATION
MUTATIONS
3111 Biomedicine
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