Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 84, Issue 3, Pages 399-405Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2009.01.026
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Funding
- Chief Scientist Office [CZB/4/540] Funding Source: researchfish
- Medical Research Council [G0800759, G0800675, G0600329] Funding Source: researchfish
- MRC [G0800759, G0600329, G0800675] Funding Source: UKRI
- Medical Research Council [G0800675, G0600329, G0800759] Funding Source: Medline
- NCATS NIH HHS [UL1 TR000077] Funding Source: Medline
- NCRR NIH HHS [C06 RR011234, M01 RR000064, M01-RR00064, M01 RR002172-26, M01 RR002172] Funding Source: Medline
- NIDDK NIH HHS [P30 DK063491-049004, DK069513, P30 DK063491, K23 DK069513] Funding Source: Medline
- Chief Scientist Office [CZB/4/540] Funding Source: Medline
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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.
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