Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

M. Beaudoin; P. Goyette; G. Boucher; K. Lo; M.A. Rivas; C.R. Stevens; A. Alikashani; M.G. Ladouceur; D. Ellinghaus; L. Törkvist; G. Goel; C. Lagacé; V. Annese; A. Bitton; J. Begun; S.R. Brant; F. Bresso; J. Cho; R.H. Duerr; J. Halfvarson; D.P.B. Mcgovern; G.L. Radford-Smith; S. Schreiber; P.L. Schumm; Y. Sharma; M.S. Silverberg; R.K. Weersma; M. D'Amato; S. Vermeire; A. Franke; G. Lettre; R.J. Xavier; M.J. Daly; J.D. Rioux; G. Aumais; E.J. Bernard; A.Y. Cohen; C. Deslandres; R.G. Lahaie; P. Paré; J.H. Cho; S.R. Targan; P.P. Schumm; P.J. Rutgeerts; S.A.F.A. Vermeire; A.H. Steinhart; T. Ahmad; C.A. Anderson; R.N. Baldassano; T. Balschun; M.L. Barclay; J.C. Barrett; T.M. Bayless; J.C.M. Bis; S. Brand; S. Bumpstead; C. Büning; A. Cohen; J.F. Colombel -; M. Cottone; R. D'Incà; T. Denson; M.C. Dubinsky; C.M. Edwards; T.H.J. Florin; D.P. Franchimont; R.B. Gearry; M.A.J.A.J. Georges; J. Glas; A. Van Gossum; A.M. Griffiths; S.L. Guthery; H.H. Hákonarson; T. Haritunians; J.P. Hugot; D.J. De Jong; L. Jostins; S. Kugathasan; G.A. Kullak- Ublick; A. Latiano; D. Laukens; Ian Lawrance; J. Lee; C.W. Lees; M. Lémann; A.D. Levine; C. Libioulle; É.J. Louis; J.C. Mansfield; C.G.P. Mathew; M. Mitrovič; G.W. Montgomery; C.E. Mowat; W.G. Newman; O. Palmieri; J. Panés; M. Parkes; A.M. Phillips; C.Y.J. Ponsioen; U. Potočnik; N.J. Prescott; D.D. Proctor; M.D. Regueiro; R.L. Roberts; J.I. Rotter; J.D. Sanderson; M. Sans; J. Satsangi; F. Seibold; L.A. Simms; K.D. Taylor; H.W. Verspaget; M.P. De Vos; T.D. Walters; K. Wang; D.C. Whiteman; C. Wijmenga

doi:10.1371/journal.pgen.1003723

Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

M. Beaudoin, P. Goyette, G. Boucher, K. Lo, M.A. Rivas, C.R. Stevens, A. Alikashani, M.G. Ladouceur, D. Ellinghaus, L. Törkvist, G. Goel, C. Lagacé, V. Annese, A. Bitton, J. Begun, S.R. Brant, F. Bresso, J. Cho, R.H. Duerr, J. HalfvarsonD.P.B. Mcgovern, G.L. Radford-Smith, S. Schreiber, P.L. Schumm, Y. Sharma, M.S. Silverberg, R.K. Weersma, M. D'Amato, S. Vermeire, A. Franke, G. Lettre, R.J. Xavier, M.J. Daly, J.D. Rioux, G. Aumais, E.J. Bernard, A.Y. Cohen, C. Deslandres, R.G. Lahaie, P. Paré, J.H. Cho, S.R. Targan, P.P. Schumm, P.J. Rutgeerts, S.A.F.A. Vermeire, A.H. Steinhart, T. Ahmad, C.A. Anderson, R.N. Baldassano, T. Balschun, M.L. Barclay, J.C. Barrett, T.M. Bayless, J.C.M. Bis, S. Brand, S. Bumpstead, C. Büning, A. Cohen, J.F. Colombel -, M. Cottone, R. D'Incà, T. Denson, M.C. Dubinsky, C.M. Edwards, T.H.J. Florin, D.P. Franchimont, R.B. Gearry, M.A.J.A.J. Georges, J. Glas, A. Van Gossum, A.M. Griffiths, S.L. Guthery, H.H. Hákonarson, T. Haritunians, J.P. Hugot, D.J. De Jong, L. Jostins, S. Kugathasan, G.A. Kullak- Ublick, A. Latiano, D. Laukens, Ian Lawrance, J. Lee, C.W. Lees, M. Lémann, A.D. Levine, C. Libioulle, É.J. Louis, J.C. Mansfield, C.G.P. Mathew, M. Mitrovič, G.W. Montgomery, C.E. Mowat, W.G. Newman, O. Palmieri, J. Panés, M. Parkes, A.M. Phillips, C.Y.J. Ponsioen, U. Potočnik, N.J. Prescott, D.D. Proctor, M.D. Regueiro, R.L. Roberts, J.I. Rotter, J.D. Sanderson, M. Sans, J. Satsangi, F. Seibold, L.A. Simms, K.D. Taylor, H.W. Verspaget, M.P. De Vos, T.D. Walters, K. Wang, D.C. Whiteman, C. Wijmenga

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Abstract

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al.

Original language	English
Pages (from-to)	11 pp.
Journal	PLoS Genetics
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1003723
Publication status	Published - 2013

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10.1371/journal.pgen.1003723

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Beaudoin, M., Goyette, P., Boucher, G., Lo, K., Rivas, M. A., Stevens, C. R., Alikashani, A., Ladouceur, M. G., Ellinghaus, D., Törkvist, L., Goel, G., Lagacé, C., Annese, V., Bitton, A., Begun, J., Brant, S. R., Bresso, F., Cho, J., Duerr, R. H., ... Wijmenga, C. (2013). Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis. PLoS Genetics, 9(9), 11 pp. https://doi.org/10.1371/journal.pgen.1003723

@article{5471f8de7d814955bec24899682bccd5,

title = "Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis",

abstract = "Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. {\textcopyright} 2013 Beaudoin et al.",

author = "M. Beaudoin and P. Goyette and G. Boucher and K. Lo and M.A. Rivas and C.R. Stevens and A. Alikashani and M.G. Ladouceur and D. Ellinghaus and L. T{\"o}rkvist and G. Goel and C. Lagac{\'e} and V. Annese and A. Bitton and J. Begun and S.R. Brant and F. Bresso and J. Cho and R.H. Duerr and J. Halfvarson and D.P.B. Mcgovern and G.L. Radford-Smith and S. Schreiber and P.L. Schumm and Y. Sharma and M.S. Silverberg and R.K. Weersma and M. D'Amato and S. Vermeire and A. Franke and G. Lettre and R.J. Xavier and M.J. Daly and J.D. Rioux and G. Aumais and E.J. Bernard and A.Y. Cohen and C. Deslandres and R.G. Lahaie and P. Par{\'e} and J.H. Cho and S.R. Targan and P.P. Schumm and P.J. Rutgeerts and S.A.F.A. Vermeire and A.H. Steinhart and T. Ahmad and C.A. Anderson and R.N. Baldassano and T. Balschun and M.L. Barclay and J.C. Barrett and T.M. Bayless and J.C.M. Bis and S. Brand and S. Bumpstead and C. B{\"u}ning and A. Cohen and {Colombel -}, J.F. and M. Cottone and R. D'Inc{\`a} and T. Denson and M.C. Dubinsky and C.M. Edwards and T.H.J. Florin and D.P. Franchimont and R.B. Gearry and M.A.J.A.J. Georges and J. Glas and {Van Gossum}, A. and A.M. Griffiths and S.L. Guthery and H.H. H{\'a}konarson and T. Haritunians and J.P. Hugot and {De Jong}, D.J. and L. Jostins and S. Kugathasan and {Kullak- Ublick}, G.A. and A. Latiano and D. Laukens and Ian Lawrance and J. Lee and C.W. Lees and M. L{\'e}mann and A.D. Levine and C. Libioulle and {\'E}.J. Louis and J.C. Mansfield and C.G.P. Mathew and M. Mitrovi{\v c} and G.W. Montgomery and C.E. Mowat and W.G. Newman and O. Palmieri and J. Pan{\'e}s and M. Parkes and A.M. Phillips and C.Y.J. Ponsioen and U. Poto{\v c}nik and N.J. Prescott and D.D. Proctor and M.D. Regueiro and R.L. Roberts and J.I. Rotter and J.D. Sanderson and M. Sans and J. Satsangi and F. Seibold and L.A. Simms and K.D. Taylor and H.W. Verspaget and {De Vos}, M.P. and T.D. Walters and K. Wang and D.C. Whiteman and C. Wijmenga",

year = "2013",

doi = "10.1371/journal.pgen.1003723",

language = "English",

volume = "9",

pages = "11 pp.",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science (PLoS)",

number = "9",

}

Beaudoin, M, Goyette, P, Boucher, G, Lo, K, Rivas, MA, Stevens, CR, Alikashani, A, Ladouceur, MG, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, J, Duerr, RH, Halfvarson, J, Mcgovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, AY, Deslandres, C, Lahaie, RG, Paré, P, Cho, JH, Targan, SR, Schumm, PP, Rutgeerts, PJ, Vermeire, SAFA, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, ML, Barrett, JC, Bayless, TM, Bis, JCM, Brand, S, Bumpstead, S, Büning, C, Cohen, A, Colombel -, JF, Cottone, M, D'Incà, R, Denson, T, Dubinsky, MC, Edwards, CM, Florin, THJ, Franchimont, DP, Gearry, RB, Georges, MAJAJ, Glas, J, Van Gossum, A, Griffiths, AM, Guthery, SL, Hákonarson, HH, Haritunians, T, Hugot, JP, De Jong, DJ, Jostins, L, Kugathasan, S, Kullak- Ublick, GA, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lémann, M, Levine, AD, Libioulle, C, Louis, ÉJ, Mansfield, JC, Mathew, CGP, Mitrovič, M, Montgomery, GW, Mowat, CE, Newman, WG, Palmieri, O, Panés, J, Parkes, M, Phillips, AM, Ponsioen, CYJ, Potočnik, U, Prescott, NJ, Proctor, DD, Regueiro, MD, Roberts, RL, Rotter, JI, Sanderson, JD, Sans, M, Satsangi, J, Seibold, F, Simms, LA, Taylor, KD, Verspaget, HW, De Vos, MP, Walters, TD, Wang, K, Whiteman, DC & Wijmenga, C 2013, 'Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis', PLoS Genetics, vol. 9, no. 9, pp. 11 pp. https://doi.org/10.1371/journal.pgen.1003723

TY - JOUR

T1 - Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

AU - Beaudoin, M.

AU - Goyette, P.

AU - Boucher, G.

AU - Lo, K.

AU - Rivas, M.A.

AU - Stevens, C.R.

AU - Alikashani, A.

AU - Ladouceur, M.G.

AU - Ellinghaus, D.

AU - Törkvist, L.

AU - Goel, G.

AU - Lagacé, C.

AU - Annese, V.

AU - Bitton, A.

AU - Begun, J.

AU - Brant, S.R.

AU - Bresso, F.

AU - Cho, J.

AU - Duerr, R.H.

AU - Halfvarson, J.

AU - Mcgovern, D.P.B.

AU - Radford-Smith, G.L.

AU - Schreiber, S.

AU - Schumm, P.L.

AU - Sharma, Y.

AU - Silverberg, M.S.

AU - Weersma, R.K.

AU - D'Amato, M.

AU - Vermeire, S.

AU - Franke, A.

AU - Lettre, G.

AU - Xavier, R.J.

AU - Daly, M.J.

AU - Rioux, J.D.

AU - Aumais, G.

AU - Bernard, E.J.

AU - Cohen, A.Y.

AU - Deslandres, C.

AU - Lahaie, R.G.

AU - Paré, P.

AU - Cho, J.H.

AU - Targan, S.R.

AU - Schumm, P.P.

AU - Rutgeerts, P.J.

AU - Vermeire, S.A.F.A.

AU - Steinhart, A.H.

AU - Ahmad, T.

AU - Anderson, C.A.

AU - Baldassano, R.N.

AU - Balschun, T.

AU - Barclay, M.L.

AU - Barrett, J.C.

AU - Bayless, T.M.

AU - Bis, J.C.M.

AU - Brand, S.

AU - Bumpstead, S.

AU - Büning, C.

AU - Cohen, A.

AU - Colombel -, J.F.

AU - Cottone, M.

AU - D'Incà, R.

AU - Denson, T.

AU - Dubinsky, M.C.

AU - Edwards, C.M.

AU - Florin, T.H.J.

AU - Franchimont, D.P.

AU - Gearry, R.B.

AU - Georges, M.A.J.A.J.

AU - Glas, J.

AU - Van Gossum, A.

AU - Griffiths, A.M.

AU - Guthery, S.L.

AU - Hákonarson, H.H.

AU - Haritunians, T.

AU - Hugot, J.P.

AU - De Jong, D.J.

AU - Jostins, L.

AU - Kugathasan, S.

AU - Kullak- Ublick, G.A.

AU - Latiano, A.

AU - Laukens, D.

AU - Lawrance, Ian

AU - Lee, J.

AU - Lees, C.W.

AU - Lémann, M.

AU - Levine, A.D.

AU - Libioulle, C.

AU - Louis, É.J.

AU - Mansfield, J.C.

AU - Mathew, C.G.P.

AU - Mitrovič, M.

AU - Montgomery, G.W.

AU - Mowat, C.E.

AU - Newman, W.G.

AU - Palmieri, O.

AU - Panés, J.

AU - Parkes, M.

AU - Phillips, A.M.

AU - Ponsioen, C.Y.J.

AU - Potočnik, U.

AU - Prescott, N.J.

AU - Proctor, D.D.

AU - Regueiro, M.D.

AU - Roberts, R.L.

AU - Rotter, J.I.

AU - Sanderson, J.D.

AU - Sans, M.

AU - Satsangi, J.

AU - Seibold, F.

AU - Simms, L.A.

AU - Taylor, K.D.

AU - Verspaget, H.W.

AU - De Vos, M.P.

AU - Walters, T.D.

AU - Wang, K.

AU - Whiteman, D.C.

AU - Wijmenga, C.

PY - 2013

Y1 - 2013

N2 - Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al.

AB - Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al.

U2 - 10.1371/journal.pgen.1003723

DO - 10.1371/journal.pgen.1003723

M3 - Article

C2 - 24068945

VL - 9

SP - 11 pp.

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

ER -

Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

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