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; Benjamin M. Neale; 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; J. Barrett; K. De Lane; C. Edwards; A. Hart; C. Hawkey; L. Jostins; N. Kennedy; C. Lamb; J. Lee; C. Lees; J. Mansfield; C. Mathew; C. Mowatt; B. Newman; E. Nimmo; M. Parkes; M. Pollard; N. Prescott; J. Randall; D. Rice; J. Satsangi; A. Simmons; M. Tremelling; H. Uhlig; D. Wilson; C. Abraham; J. P. Achkar; A. Bitton; G. Boucher; K. Croitoru; P. Fleshner; J. Glas; S. Kugathasan; J. V. Limbergen; R. Milgrom; D. Proctor; M. Regueiro; P. L. Schumm; Y. Sharma; J. M. Stempak; S. R. Targan; M. H. Wang

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, Benjamin M. Neale, 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, J. Barrett, K. De Lane, C. Edwards, A. Hart, C. Hawkey, L. Jostins, N. Kennedy, C. Lamb, J. Lee, C. Lees (Member of Consortium), J. Mansfield, C. Mathew, C. Mowatt, B. Newman, E. Nimmo (Member of Consortium), M. Parkes, M. Pollard, N. Prescott, J. Randall, D. Rice, J. Satsangi (Member of Consortium), A. Simmons, M. Tremelling, H. Uhlig, D. Wilson, C. Abraham, J. P. Achkar, A. Bitton, G. Boucher, K. Croitoru, P. Fleshner, J. Glas, S. Kugathasan, J. V. Limbergen, R. Milgrom, D. Proctor, M. Regueiro, P. L. Schumm, Y. Sharma, J. M. Stempak, S. R. Targan, M. H. Wang

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 â '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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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., ... Wang, M. H. (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 {\^a} '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 Neale, {Benjamin M.} 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 J. Barrett and {De Lane}, K. and C. Edwards and A. Hart and C. Hawkey and L. Jostins and N. Kennedy and C. Lamb and J. Lee and C. Lees and J. Mansfield and C. Mathew and C. Mowatt and B. Newman and E. Nimmo and M. Parkes and M. Pollard and N. Prescott and J. Randall and D. Rice and J. Satsangi and A. Simmons and M. Tremelling and H. Uhlig and D. Wilson and C. Abraham and Achkar, {J. P.} and A. Bitton and G. Boucher and K. Croitoru and P. Fleshner and J. Glas and S. Kugathasan and Limbergen, {J. V.} and R. Milgrom and D. Proctor and M. Regueiro and Schumm, {P. L.} and Y. Sharma and Stempak, {J. M.} and Targan, {S. R.} and Wang, {M. H.}",

year = "2016",

month = aug,

day = "9",

doi = "10.1038/ncomms12342",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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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, Neale, BM, 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, Barrett, J, De Lane, K, Edwards, C, Hart, A, Hawkey, C, Jostins, L, Kennedy, N, Lamb, C, Lee, J, Lees, C, Mansfield, J, Mathew, C, Mowatt, C, Newman, B, Nimmo, E, Parkes, M, Pollard, M, Prescott, N, Randall, J, Rice, D, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, D, Abraham, C, Achkar, JP, Bitton, A, Boucher, G, Croitoru, K, Fleshner, P, Glas, J, Kugathasan, S, Limbergen, JV, Milgrom, R, Proctor, D, Regueiro, M, Schumm, PL, Sharma, Y, Stempak, JM, Targan, SR & Wang, MH 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 - Neale, Benjamin M.

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 - Barrett, J.

AU - De Lane, K.

AU - Edwards, C.

AU - Hart, A.

AU - Hawkey, C.

AU - Jostins, L.

AU - Kennedy, N.

AU - Lamb, C.

AU - Lee, J.

AU - Mansfield, J.

AU - Mathew, C.

AU - Mowatt, C.

AU - Newman, B.

AU - Parkes, M.

AU - Pollard, M.

AU - Prescott, N.

AU - Randall, J.

AU - Rice, D.

AU - Simmons, A.

AU - Tremelling, M.

AU - Uhlig, H.

AU - Wilson, D.

AU - Abraham, C.

AU - Achkar, J. P.

AU - Bitton, A.

AU - Boucher, G.

AU - Croitoru, K.

AU - Fleshner, P.

AU - Glas, J.

AU - Kugathasan, S.

AU - Limbergen, J. V.

AU - Milgrom, R.

AU - Proctor, D.

AU - Regueiro, M.

AU - Schumm, P. L.

AU - Sharma, Y.

AU - Stempak, J. M.

AU - Targan, S. R.

AU - Wang, M. H.

A2 - Lees, C.

A2 - Nimmo, E.

A2 - Satsangi, J.

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 â '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 â '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.

UR - http://www.scopus.com/inward/record.url?scp=84981165781&partnerID=8YFLogxK

U2 - 10.1038/ncomms12342

DO - 10.1038/ncomms12342

M3 - Article

AN - SCOPUS:84981165781

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

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