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

• Published in: Nature communications Vol. 7; no. 1; p. 12342
• Main Authors: Rivas, Manuel A., Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, A. Nicole, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Sören, Kurki, Mitja I., Li, Dalin, D’Amato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse K., Halfvarson, Jonas, Paavola-Sakki, Paulina, Lappalainen, 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, Päivi, Kontula, Kimmo, Färkkilä, Martti, McGovern, Dermot P. B., Franke, Andre, Stefansson, Kari, Rioux, John D., Xavier, Ramnik J., Daly, Mark J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-08-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/205/2138; 692/4020/1503/257/1389; Alleles; Colitis, Ulcerative - genetics; Colitis, Ulcerative - prevention & control; Consortia; Gastroenterology; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Genetics; Genomes; Hepatology; Hospitals; Humanities and Social Sciences; Humans; Inflammatory bowel disease; Medicin och hälsovetenskap; Medicine; multidisciplinary; Mutation - genetics; Protein Transport; Proteins; Public health; Reproducibility of Results; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Sequence Analysis, DNA; Ubiquitin-Protein Ligases - genetics; United Kingdom > UK; United States > US; California; Iceland; Pennsylvania; Canada; Los Angeles California; Sweden; Belgium; Massachusetts; Finland; Italy; Pittsburgh Pennsylvania; Maryland; Baltimore Maryland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12342

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
−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.
While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients’ genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in
RNF186
to be protective against UC.