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; Soeren Mucha; Mitja I. Kurki; Dalin Li; Mauro D'Amato; Vito Annese; Severine Vermeire; Rinse K. Weersma; Jonas Halfvarson; Paulina Paavola-Sakki; Maarit Lappalainen; Monkol Lek; Beryl Cummings; Taru Tukiainen; Talin Haritunians; Leena Halme; Lotta L. E. Koskinen; Ashwin N. Ananthakrishnan; Yang Luo; Graham A. Heap; Marijn C. Visschedijk; 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; Paivi Saavalainen; Kimmo Kontula; Martti Farkkila; Dermot P. B. McGovern; Andre Franke; Kari Stefansson; John D. Rioux; Ramnik J. Xavier; Mark J. Daly; NIDDK IBD Genetics Consortium

doi:10.1038/ncomms12342

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

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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, …

Nature communications, Vol.7(1), pp.12342-12342

09/08/2016

DOI: https://doi.org/10.1038/ncomms12342

PMCID: PMC4980482

PMID: 27503255

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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.

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Title: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Creators - without role: Manuel A. Rivas - Broad Institute
Daniel Graham - Broad Institute
Patrick Sulem - Amgen Inc, DeCODE Genet, IS-101 Reykjavik, Iceland
Christine Stevens - Broad Institute
A. Nicole Desch - Broad Institute
Philippe Goyette - Montreal Heart Institute
Daniel Gudbjartsson - Amgen Inc, DeCODE Genet, IS-101 Reykjavik, Iceland
Ingileif Jonsdottir - Amgen Inc, DeCODE Genet, IS-101 Reykjavik, Iceland
Unnur Thorsteinsdottir - Amgen Inc, DeCODE Genet, IS-101 Reykjavik, Iceland
Frauke Degenhardt - Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany
Soeren Mucha - Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany
Mitja I. Kurki - Broad Institute
Dalin Li - College Station Medical Center
Mauro D'Amato - Karolinska Institutet
Vito Annese - CASA
Severine Vermeire - KU Leuven
Rinse K. Weersma - University of Groningen
Jonas Halfvarson - College Station Medical Center
Paulina Paavola-Sakki - University of Helsinki
Maarit Lappalainen - University of Helsinki
Monkol Lek - Broad Institute
Beryl Cummings - Broad Institute
Taru Tukiainen - Broad Institute
Talin Haritunians - College Station Medical Center
Leena Halme - University of Helsinki
Lotta L. E. Koskinen - University of Helsinki
Ashwin N. Ananthakrishnan - Supreme Council Of Health
Yang Luo - Wellcome Sanger Institute
Graham A. Heap - Phillips Exeter Academy
Marijn C. Visschedijk - University of Groningen
Daniel G. MacArthur - Supreme Council Of Health
Benjamin M. Neale - Supreme Council Of Health
Tariq Ahmad - Phillips Exeter Academy
Carl A. Anderson - Wellcome Sanger Institute
Steven R. Brant - Johns Hopkins University
Richard H. Duerr - University of Pittsburgh
Mark S. Silverberg - College Station Medical Center
Judy H. Cho - Supreme Council Of Health
Aarno Palotie - Ikerbasque
Paivi Saavalainen - University of Helsinki
Kimmo Kontula - University of Helsinki
Martti Farkkila - University of Helsinki
Dermot P. B. McGovern - College Station Medical Center
Andre Franke - Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany
Kari Stefansson - Amgen
John D. Rioux - College Station Medical Center
Ramnik J. Xavier - Broad Institute
Mark J. Daly - Broad Institute
NIDDK IBD Genetics Consortium
Publication Details: Nature communications, Vol.7(1), pp.12342-12342
Publisher: Springer Nature
Number of pages: 7
Grant note: Crohn's and Colitis Foundation of America 2013583217 / Amgen DK064869; DK062432 / National Institute of Diabetes and Digestive and Kidney Disease (NIDDK); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) ETM/137 / Chief Scientist Office DK062413; AI067068; U54DE023789-01; 305479 / European Union; European Commission; Spanish Government MR/J00314X/1 / Medical Research Council, UK; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh NIHR-RP-R3-12-026; ACF-2014-23-002 / National Institute for Health Research; National Institute for Health & Care Research (NIHR) Cedars-Sinai F. Widjaja Foundation WT091310; 098051 / Wellcome Trust G0800759; MR/J00314X/1; G0600329; MC_UU_12010/7 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) DK064869; DK043351; HG005923 / National Human Genome Research Institute (NHGRI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) 2015PG-IBD001 / Leona M. AMP; Harry B. Helmsley Charitable Trust Leona M. and Harry B. Helmsley Charitable Trust MR/J00314X/1; MC_UU_12010/7; G0800759; G0600329 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 3765 / Crohns and Colitis Foundation DK062431; U01 DK062429; U01 DK062422; R01 DK092235; U01 DK062420 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 3765 / CCFA
Identifiers: 9925127108331
Academic Unit: Prince Sattam Bin Abdulaziz University
Language: English
Resource Type: Journal article