Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease.
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 CD, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests. The observed pathway-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.
Wang
Kai
K
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Zhang
Haitao
H
Kugathasan
Subra
S
Annese
Vito
V
Bradfield
Jonathan P
JP
Russell
Richard K
RK
Sleiman
Patrick M A
PM
Imielinski
Marcin
M
Glessner
Joseph
J
Hou
Cuiping
C
Wilson
David C
DC
Walters
Thomas
T
Kim
Cecilia
C
Frackelton
Edward C
EC
Lionetti
Paolo
P
Barabino
Arrigo
A
Van Limbergen
Johan
J
Guthery
Stephen
S
Denson
Lee
L
Piccoli
David
D
Li
Mingyao
M
Dubinsky
Marla
M
Silverberg
Mark
M
Griffiths
Anne
A
Grant
Struan F A
SF
Satsangi
Jack
J
Baldassano
Robert
R
Hakonarson
Hakon
H
D003424:Crohn Disease / Q000235:genetics*; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D053759:Interleukin-23 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
D053759:Interleukin-23; D018664:Interleukin-12