New Results
A protein truncating R179X variant in RNF186 confers protection against ulcerative colitis
MA Rivas, D Graham, P Sulem, C Stevens, AN Desch, P Goyette, D Gudbjartsson, I Jonsdottir, U Thorsteinsdottir, F Degenhardt, S Mucha, MI Kurki, D Li, M D’Amato, V Annese, S Vermeire, R Weersma, J Halfvarson, P Paavola-Sakki, M Lappalainen, M Lek, B Cummings, T Tukianen, T Haritunians, L Halme, LLE Koskinen, A Ananthakrishnan, Y Luo, GA Heap, M Visschedijk, NIDDK IBD Genetics Consortium, UK IBD Genetics Consortium, DG MacArthur, BM Neale, T Ahmad, CA Anderson, SR Brant, R Duerr, M Silverberg, J Cho, A Palotie, P Saavalainen, K Kontula, M Färkkilä, DPB McGovern, A Franke, K Stefansson, JD Rioux, RJ Xavier, MJ Daly
doi: https://doi.org/10.1101/035105
MA Rivas
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
D Graham
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
P Sulem
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
C Stevens
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
AN Desch
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
P Goyette
4Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
D Gudbjartsson
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
5School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
I Jonsdottir
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
6Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.
7Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
U Thorsteinsdottir
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
7Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
F Degenhardt
8Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
S Mucha
8Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
MI Kurki
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
D Li
9Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
M D’Amato
10Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
11BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
V Annese
12Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy.
13Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy.
S Vermeire
14Department of Clinical and experimental medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven, Belgium.
15Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
R Weersma
16Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
J Halfvarson
17Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
P Paavola-Sakki
18Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
19Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
M Lappalainen
18Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
20Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
M Lek
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
B Cummings
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
T Tukianen
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
T Haritunians
21F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
L Halme
22Department of Transplantation and Liver Surgery, University of Helsinki, Helsinki, Finland.
LLE Koskinen
20Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
23Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
A Ananthakrishnan
24Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
25Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
Y Luo
26Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
GA Heap
27IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter, UK.
M Visschedijk
16Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.
DG MacArthur
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
BM Neale
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
T Ahmad
28Peninsula College of Medicine and Dentistry, Exeter, UK.
CA Anderson
26Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
SR Brant
29Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine and the Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
R Duerr
30Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
31Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
M Silverberg
32Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada.
J Cho
33Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
A Palotie
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
34Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
35Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts, USA.
P Saavalainen
36Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.
K Kontula
18Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
M Färkkilä
18Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
19Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
DPB McGovern
21F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
A Franke
8Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
K Stefansson
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
7Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
JD Rioux
3deCODE Genetics, Amgen inc., Reykjavik, Iceland.
37Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
RJ Xavier
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
24Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
MJ Daly
1Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract
We conducted a search for protein truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. We found that a 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 = 6.89×10−7, odds ratio (OR) = 0.30). We further demonstrate that the truncated protein is expressed, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization or loss of an essential protein element.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted December 23, 2015.
A protein truncating R179X variant in RNF186 confers protection against ulcerative colitis
MA Rivas, D Graham, P Sulem, C Stevens, AN Desch, P Goyette, D Gudbjartsson, I Jonsdottir, U Thorsteinsdottir, F Degenhardt, S Mucha, MI Kurki, D Li, M D’Amato, V Annese, S Vermeire, R Weersma, J Halfvarson, P Paavola-Sakki, M Lappalainen, M Lek, B Cummings, T Tukianen, T Haritunians, L Halme, LLE Koskinen, A Ananthakrishnan, Y Luo, GA Heap, M Visschedijk, NIDDK IBD Genetics Consortium, UK IBD Genetics Consortium, DG MacArthur, BM Neale, T Ahmad, CA Anderson, SR Brant, R Duerr, M Silverberg, J Cho, A Palotie, P Saavalainen, K Kontula, M Färkkilä, DPB McGovern, A Franke, K Stefansson, JD Rioux, RJ Xavier, MJ Daly
bioRxiv 035105; doi: https://doi.org/10.1101/035105
A protein truncating R179X variant in RNF186 confers protection against ulcerative colitis
MA Rivas, D Graham, P Sulem, C Stevens, AN Desch, P Goyette, D Gudbjartsson, I Jonsdottir, U Thorsteinsdottir, F Degenhardt, S Mucha, MI Kurki, D Li, M D’Amato, V Annese, S Vermeire, R Weersma, J Halfvarson, P Paavola-Sakki, M Lappalainen, M Lek, B Cummings, T Tukianen, T Haritunians, L Halme, LLE Koskinen, A Ananthakrishnan, Y Luo, GA Heap, M Visschedijk, NIDDK IBD Genetics Consortium, UK IBD Genetics Consortium, DG MacArthur, BM Neale, T Ahmad, CA Anderson, SR Brant, R Duerr, M Silverberg, J Cho, A Palotie, P Saavalainen, K Kontula, M Färkkilä, DPB McGovern, A Franke, K Stefansson, JD Rioux, RJ Xavier, MJ Daly
bioRxiv 035105; doi: https://doi.org/10.1101/035105
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