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

被引：236

作者：

Wang, Kai ^{[1
]}

Zhang, Haitao ^{[1
]}

Kugathasan, Subra ^{[2
]}

Annese, Vito ^{[3
]}

Bradfield, Jonathan R. ^{[1
]}

Russell, Richard K. ^{[4
]}

Sleiman, Patrick M. A. ^{[1
]}

Imielinski, Marcin ^{[1
]}

Glessner, Joseph ^{[1
]}

Hou, Cuiping ^{[1
]}

Wilson, David C. ^{[6
]}

Walters, Thomas ^{[5
]}

Kim, Cecilia ^{[1
]}

Frackelton, Edward C. ^{[1
]}

Lionetti, Paolo ^{[7
]}

Barabino, Arrigo ^{[8
]}

Van Limbergen, Johan ^{[9
]}

Guthery, Stephen ^{[10
,11
]}

Denson, Lee ^{[12
]}

Piccoli, David ^{[13
,14
]}

Li, Mingyao ^{[15
]}

Dubinsky, Marla ^{[16
]}

Silverberg, Mark ^{[17
]}

Griffiths, Anne

Grant, Stiruan F. A. ^{[1
,18
]}

Satsangi, Jack

Baldassano, Robert ^{[13
,14
]}

Hakonarson, Hakon ^{[1
,18
]}

机构：

[1] Childrens Hosp, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Emory Clin, Sch Med & Childrens Hlth Care Atlanta, Dept Pediat, Atlanta, GA 30322 USA

[3] CSS Hosp, IRCCS, Units Gastroenterol & Endoscopy, I-71013 San Giovanni Rotondo, Italy

[4] Yorkhill Hosp, Dept Paediat Gastroenterrol, Glasgow G3 8SJ, Lanark, Scotland

[5] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[6] Univ Edinburgh, Edinburgh EI14 2XU, Midlothian, Scotland

[7] Univ Hosp Meyer, Dept Pediat, I-50139 Florence, Italy

[8] Gaslini Hosp, Unit Pediat 3, I-16147 Genoa, Italy

[9] Univ Edinburgh, Western Gen Hosp, Gastrointestinal Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[10] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84132 USA

[11] Primary Childrens Med Ctr, Salt Lake City, UT 84132 USA

[12] Cincinnati Childrens Hosp, Med Ctr, Div Gastroenterol, Cincinnati, OH 45229 USA

[13] Childrens Hosp Philadelphia, Div Gastroenterol, Philadelphia, PA 19104 USA

[14] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[15] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[16] Cedars Sinai Med Ctr, Dept Pediat & Common Dis Genet, Los Angeles, CA 90048 USA

[17] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada

[18] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2009年 / 84卷 / 03期

基金：

英国医学研究理事会;

关键词：

INFLAMMATORY-BOWEL-DISEASE; SUSCEPTIBILITY LOCI; VARIANTS; METAANALYSIS; EXPRESSION; ANTIBODY; RECEPTOR; GENES; IL-23; TOOL;

D O I：

10.1016/j.ajhg.2009.01.026

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：399 / 405

页数：7

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