Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Manuel A. Rivas; Mélissa Beaudoin; Agnes Gardet; Christine Stevens; Yashoda Sharma; Clarence K. Zhang; Gabrielle Boucher; Stephan Ripke; David Ellinghaus; Noel Burtt; Tim Fennell; Andrew Kirby; Anna Latiano; Philippe Goyette; Todd Green; Jonas Halfvarson; Talin Haritunians; Joshua M. Korn; Finny Kuruvilla; Caroline Lagacé; Benjamin Neale; Ken Sin Lo; Phil Schumm; Leif Törkvist; National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC); International Inflammatory Bowel Disease Genetics Consortium; Marla C. Dubinsky; Steven R. Brant; Mark S. Silverberg; Richard H. Duerr; David Altshuler; Stacey Gabriel; Guillaume Lettre; Andre Franke; Mauro D'Amato; Dermot P.B. McGovern; Judy H. Cho; John D. Rioux; Ramnik J. Xavier; Mark J. Daly; Craig Mowat

doi:10.1038/ng.952

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Manuel A. Rivas (Lead / Corresponding author), Mélissa Beaudoin, Agnes Gardet, Christine Stevens, Yashoda Sharma, Clarence K. Zhang, Gabrielle Boucher, Stephan Ripke, David Ellinghaus, Noel Burtt, Tim Fennell, Andrew Kirby, Anna Latiano, Philippe Goyette, Todd Green, Jonas Halfvarson, Talin Haritunians, Joshua M. Korn, Finny Kuruvilla, Caroline LagacéBenjamin Neale, Ken Sin Lo, Phil Schumm, Leif Törkvist, National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC), , International Inflammatory Bowel Disease Genetics Consortium, Marla C. Dubinsky, Steven R. Brant, Mark S. Silverberg, Richard H. Duerr, David Altshuler, Stacey Gabriel, Guillaume Lettre, Andre Franke, Mauro D'Amato, Dermot P.B. McGovern, Judy H. Cho, John D. Rioux, Ramnik J. Xavier, Mark J. Daly (Lead / Corresponding author), Craig Mowat (Contributing member)

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Abstract

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 ^-16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

Original language	English
Pages (from-to)	1066-1073
Number of pages	8
Journal	Nature Genetics
Volume	43
Issue number	11
Early online date	9 Oct 2011
DOIs	https://doi.org/10.1038/ng.952
Publication status	Published - Nov 2011

ASJC Scopus subject areas

Genetics

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Rivas, M. A., Beaudoin, M., Gardet, A., Stevens, C., Sharma, Y., Zhang, C. K., Boucher, G., Ripke, S., Ellinghaus, D., Burtt, N., Fennell, T., Kirby, A., Latiano, A., Goyette, P., Green, T., Halfvarson, J., Haritunians, T., Korn, J. M., Kuruvilla, F., ... Mowat, C. (2011). Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nature Genetics, 43(11), 1066-1073. https://doi.org/10.1038/ng.952

@article{d7414fef0b1242bd93b672618b2429e9,

title = "Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease",

abstract = "More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 -16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.",

author = "Rivas, {Manuel A.} and M{\'e}lissa Beaudoin and Agnes Gardet and Christine Stevens and Yashoda Sharma and Zhang, {Clarence K.} and Gabrielle Boucher and Stephan Ripke and David Ellinghaus and Noel Burtt and Tim Fennell and Andrew Kirby and Anna Latiano and Philippe Goyette and Todd Green and Jonas Halfvarson and Talin Haritunians and Korn, {Joshua M.} and Finny Kuruvilla and Caroline Lagac{\'e} and Benjamin Neale and Lo, {Ken Sin} and Phil Schumm and Leif T{\"o}rkvist and {National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC)} and {International Inflammatory Bowel Disease Genetics Consortium} and Dubinsky, {Marla C.} and Brant, {Steven R.} and Silverberg, {Mark S.} and Duerr, {Richard H.} and David Altshuler and Stacey Gabriel and Guillaume Lettre and Andre Franke and Mauro D'Amato and McGovern, {Dermot P.B.} and Cho, {Judy H.} and Rioux, {John D.} and Xavier, {Ramnik J.} and Daly, {Mark J.} and Craig Mowat",

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Rivas, MA, Beaudoin, M, Gardet, A, Stevens, C, Sharma, Y, Zhang, CK, Boucher, G, Ripke, S, Ellinghaus, D, Burtt, N, Fennell, T, Kirby, A, Latiano, A, Goyette, P, Green, T, Halfvarson, J, Haritunians, T, Korn, JM, Kuruvilla, F, Lagacé, C, Neale, B, Lo, KS, Schumm, P, Törkvist, L, National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC), International Inflammatory Bowel Disease Genetics Consortium, Dubinsky, MC, Brant, SR, Silverberg, MS, Duerr, RH, Altshuler, D, Gabriel, S, Lettre, G, Franke, A, D'Amato, M, McGovern, DPB, Cho, JH, Rioux, JD, Xavier, RJ & Daly, MJ & Mowat, C 2011, 'Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease', Nature Genetics, vol. 43, no. 11, pp. 1066-1073. https://doi.org/10.1038/ng.952

TY - JOUR

T1 - Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

AU - Rivas, Manuel A.

AU - Beaudoin, Mélissa

AU - Gardet, Agnes

AU - Stevens, Christine

AU - Sharma, Yashoda

AU - Zhang, Clarence K.

AU - Boucher, Gabrielle

AU - Ripke, Stephan

AU - Ellinghaus, David

AU - Burtt, Noel

AU - Fennell, Tim

AU - Kirby, Andrew

AU - Latiano, Anna

AU - Goyette, Philippe

AU - Green, Todd

AU - Halfvarson, Jonas

AU - Haritunians, Talin

AU - Korn, Joshua M.

AU - Kuruvilla, Finny

AU - Lagacé, Caroline

AU - Neale, Benjamin

AU - Lo, Ken Sin

AU - Schumm, Phil

AU - Törkvist, Leif

AU - National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC)

AU - International Inflammatory Bowel Disease Genetics Consortium

AU - Dubinsky, Marla C.

AU - Brant, Steven R.

AU - Silverberg, Mark S.

AU - Duerr, Richard H.

AU - Altshuler, David

AU - Gabriel, Stacey

AU - Lettre, Guillaume

AU - Franke, Andre

AU - D'Amato, Mauro

AU - McGovern, Dermot P.B.

AU - Cho, Judy H.

AU - Rioux, John D.

AU - Xavier, Ramnik J.

AU - Daly, Mark J.

A2 - Mowat, Craig

PY - 2011/11

Y1 - 2011/11

N2 - More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 -16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

AB - More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 -16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

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JO - Nature Genetics

JF - Nature Genetics

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Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

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