Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease

Kai Wang; Haitao Zhang; Subra Kugathasan; Vito Annese; Jonathan R. Bradfield; Richard K. Russell; Patrick M. A. Sleiman; Marcin Imielinski; Joseph Glessner; Cuiping Hou; David C. Wilson; Thomas Walters; Cecilia Kim; Edward C. Frackelton; Paolo Lionetti; Arrigo Barabino; Johan Van Limbergen; Stephen Guthery; Lee Denson; David Piccoli; Mingyao Li; Marla Dubinsky; Mark Silverberg; Anne Griffiths; Stiruan F. A. Grant; Jack Satsangi; Robert Baldassano; Hakon Hakonarson

doi:10.1016/j.ajhg.2009.01.026

Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease

Kai Wang, Haitao Zhang, Subra Kugathasan, Vito Annese, Jonathan R. Bradfield, Richard K. Russell, Patrick M. A. Sleiman, Marcin Imielinski, Joseph Glessner, Cuiping Hou, David C. Wilson, Thomas Walters, Cecilia Kim, Edward C. Frackelton, Paolo Lionetti, Arrigo Barabino, Johan Van Limbergen, Stephen Guthery, Lee Denson, David PiccoliMingyao Li, Marla Dubinsky, Mark Silverberg, Anne Griffiths, Stiruan F. A. Grant, Jack Satsangi, Robert Baldassano, Hakon Hakonarson

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

Abstract / Description of output

Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 X 10 (5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently Identified as genuine susceptibility genes only through meta-analysis of several GWA Studies. In addition, the pathway contains other susceptibility genes for CID, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests.The observed path way-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our Study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.

Original language	English
Pages (from-to)	399-405
Number of pages	7
Journal	American Journal of Human Genetics
Volume	84
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2009.01.026
Publication status	Published - 13 Mar 2009

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Wang, K., Zhang, H., Kugathasan, S., Annese, V., Bradfield, J. R., Russell, R. K., Sleiman, P. M. A., Imielinski, M., Glessner, J., Hou, C., Wilson, D. C., Walters, T., Kim, C., Frackelton, E. C., Lionetti, P., Barabino, A., Van Limbergen, J., Guthery, S., Denson, L., ... Hakonarson, H. (2009). Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease. American Journal of Human Genetics, 84(3), 399-405. https://doi.org/10.1016/j.ajhg.2009.01.026

@article{5f2578aa84fb481082c89d38533385c1,

title = "Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease",

abstract = "Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 X 10 (5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently Identified as genuine susceptibility genes only through meta-analysis of several GWA Studies. In addition, the pathway contains other susceptibility genes for CID, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests.The observed path way-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our Study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.",

author = "Kai Wang and Haitao Zhang and Subra Kugathasan and Vito Annese and Bradfield, {Jonathan R.} and Russell, {Richard K.} and Sleiman, {Patrick M. A.} and Marcin Imielinski and Joseph Glessner and Cuiping Hou and Wilson, {David C.} and Thomas Walters and Cecilia Kim and Frackelton, {Edward C.} and Paolo Lionetti and Arrigo Barabino and {Van Limbergen}, Johan and Stephen Guthery and Lee Denson and David Piccoli and Mingyao Li and Marla Dubinsky and Mark Silverberg and Anne Griffiths and Grant, {Stiruan F. A.} and Jack Satsangi and Robert Baldassano and Hakon Hakonarson",

year = "2009",

month = mar,

day = "13",

doi = "10.1016/j.ajhg.2009.01.026",

language = "English",

volume = "84",

pages = "399--405",

journal = "American Journal of Human Genetics",

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publisher = "Cell Press",

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Wang, K, Zhang, H, Kugathasan, S, Annese, V, Bradfield, JR, Russell, RK, Sleiman, PMA, Imielinski, M, Glessner, J, Hou, C, Wilson, DC, Walters, T, Kim, C, Frackelton, EC, Lionetti, P, Barabino, A, Van Limbergen, J, Guthery, S, Denson, L, Piccoli, D, Li, M, Dubinsky, M, Silverberg, M, Griffiths, A, Grant, SFA, Satsangi, J, Baldassano, R & Hakonarson, H 2009, 'Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease', American Journal of Human Genetics, vol. 84, no. 3, pp. 399-405. https://doi.org/10.1016/j.ajhg.2009.01.026

TY - JOUR

T1 - Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease

AU - Wang, Kai

AU - Zhang, Haitao

AU - Kugathasan, Subra

AU - Annese, Vito

AU - Bradfield, Jonathan R.

AU - Russell, Richard K.

AU - Sleiman, Patrick M. A.

AU - Imielinski, Marcin

AU - Glessner, Joseph

AU - Hou, Cuiping

AU - Wilson, David C.

AU - Walters, Thomas

AU - Kim, Cecilia

AU - Frackelton, Edward C.

AU - Lionetti, Paolo

AU - Barabino, Arrigo

AU - Van Limbergen, Johan

AU - Guthery, Stephen

AU - Denson, Lee

AU - Piccoli, David

AU - Li, Mingyao

AU - Dubinsky, Marla

AU - Silverberg, Mark

AU - Griffiths, Anne

AU - Grant, Stiruan F. A.

AU - Satsangi, Jack

AU - Baldassano, Robert

AU - Hakonarson, Hakon

PY - 2009/3/13

Y1 - 2009/3/13

N2 - Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 X 10 (5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently Identified as genuine susceptibility genes only through meta-analysis of several GWA Studies. In addition, the pathway contains other susceptibility genes for CID, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests.The observed path way-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our Study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.

AB - Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 X 10 (5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently Identified as genuine susceptibility genes only through meta-analysis of several GWA Studies. In addition, the pathway contains other susceptibility genes for CID, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests.The observed path way-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our Study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.

U2 - 10.1016/j.ajhg.2009.01.026

DO - 10.1016/j.ajhg.2009.01.026

M3 - Article

SN - 0002-9297

VL - 84

SP - 399

EP - 405

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease

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