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 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; 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; C Hawkey; C Mathew; N Prescott; UK IBD Genetics Consortium

doi:10.1038/ncomms12342

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, Daniel G MacArthur, 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, C Hawkey, C Mathew, N Prescott, UK IBD Genetics Consortium

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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 × 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.

Original language	English
Article number	12342
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12342
Publication status	Published - 9 Aug 2016

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A protein-truncating R179X_RIVAS_Accepted 24Jun2016_GOLD VoRFinal published version, 380 KBLicence: CC BY

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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, P., ... UK IBD Genetics Consortium (2016). A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nature Communications, 7, Article 12342. https://doi.org/10.1038/ncomms12342

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title = "A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis",

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 × 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.",

author = "Rivas, {Manuel A} and Daniel Graham and Patrick Sulem and Christine Stevens and Desch, {A Nicole} and Philippe Goyette and Daniel Gudbjartsson and Ingileif Jonsdottir and Unnur Thorsteinsdottir and Frauke Degenhardt and S{\"o}ren Mucha and Kurki, {Mitja I} and Dalin Li and Mauro D'Amato and Vito Annese and Severine Vermeire and Weersma, {Rinse K} and Jonas Halfvarson and Paulina Paavola-Sakki and Maarit Lappalainen and Monkol Lek and Beryl Cummings and Taru Tukiainen and Talin Haritunians and Leena Halme and Koskinen, {Lotta L E} and Ananthakrishnan, {Ashwin N} and Yang Luo and Heap, {Graham A} and Visschedijk, {Marijn C} and MacArthur, {Daniel G} and Tariq Ahmad and Anderson, {Carl A} and Brant, {Steven R} and Duerr, {Richard H} and Silverberg, {Mark S} and Cho, {Judy H} and Aarno Palotie and P{\"a}ivi Saavalainen and Kimmo Kontula and Martti F{\"a}rkkil{\"a} and McGovern, {Dermot P B} and Andre Franke and Kari Stefansson and Rioux, {John D} and Xavier, {Ramnik J} and Daly, {Mark J} and C Hawkey and C Mathew and N Prescott and {UK IBD Genetics Consortium}",

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Rivas, MA, Graham, D, Sulem, P, Stevens, C, Desch, AN, Goyette, P, Gudbjartsson, D, Jonsdottir, I, Thorsteinsdottir, U, Degenhardt, F, Mucha, S, Kurki, MI, Li, D, D'Amato, M, Annese, V, Vermeire, S, Weersma, RK, Halfvarson, J, Paavola-Sakki, P, Lappalainen, M, Lek, M, Cummings, B, Tukiainen, T, Haritunians, T, Halme, L, Koskinen, LLE, Ananthakrishnan, AN, Luo, Y, Heap, GA, Visschedijk, MC, MacArthur, DG, Ahmad, T, Anderson, CA, Brant, SR, Duerr, RH, Silverberg, MS, Cho, JH, Palotie, A, Saavalainen, P, Kontula, K, Färkkilä, M, McGovern, DPB, Franke, A, Stefansson, K, Rioux, JD, Xavier, RJ, Daly, MJ, Hawkey, C , Mathew, C , Prescott, N & UK IBD Genetics Consortium 2016, 'A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis', Nature Communications, vol. 7, 12342. https://doi.org/10.1038/ncomms12342

TY - JOUR

T1 - A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

AU - Rivas, Manuel A

AU - Graham, Daniel

AU - Sulem, Patrick

AU - Stevens, Christine

AU - Desch, A Nicole

AU - Goyette, Philippe

AU - Gudbjartsson, Daniel

AU - Jonsdottir, Ingileif

AU - Thorsteinsdottir, Unnur

AU - Degenhardt, Frauke

AU - Mucha, Sören

AU - Kurki, Mitja I

AU - Li, Dalin

AU - D'Amato, Mauro

AU - Annese, Vito

AU - Vermeire, Severine

AU - Weersma, Rinse K

AU - Halfvarson, Jonas

AU - Paavola-Sakki, Paulina

AU - Lappalainen, Maarit

AU - Lek, Monkol

AU - Cummings, Beryl

AU - Tukiainen, Taru

AU - Haritunians, Talin

AU - Halme, Leena

AU - Koskinen, Lotta L E

AU - Ananthakrishnan, Ashwin N

AU - Luo, Yang

AU - Heap, Graham A

AU - Visschedijk, Marijn C

AU - MacArthur, Daniel G

AU - Ahmad, Tariq

AU - Anderson, Carl A

AU - Brant, Steven R

AU - Duerr, Richard H

AU - Silverberg, Mark S

AU - Cho, Judy H

AU - Palotie, Aarno

AU - Saavalainen, Päivi

AU - Kontula, Kimmo

AU - Färkkilä, Martti

AU - McGovern, Dermot P B

AU - Franke, Andre

AU - Stefansson, Kari

AU - Rioux, John D

AU - Xavier, Ramnik J

AU - Daly, Mark J

AU - Hawkey, C

AU - Mathew, C

AU - Prescott, N

AU - UK IBD Genetics Consortium

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms12342

DO - 10.1038/ncomms12342

M3 - Article

C2 - 27503255

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12342

ER -

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

Abstract

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