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 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.
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Richard K
authors.initials: RK
authors.lastname: Russell
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.forename: Thomas
authors.initials: T
authors.lastname: Walters
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Paolo
authors.initials: P
authors.lastname: Lionetti
authors.forename: Arrigo
authors.initials: A
authors.lastname: Barabino
authors.forename: Johan
authors.initials: J
authors.lastname: Van Limbergen
authors.forename: Stephen
authors.initials: S
authors.lastname: Guthery
authors.forename: Lee
authors.initials: L
authors.lastname: Denson
authors.forename: David
authors.initials: D
authors.lastname: Piccoli
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.forename: Mark
authors.initials: M
authors.lastname: Silverberg
authors.forename: Anne
authors.initials: A
authors.lastname: Griffiths
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.forename: Robert
authors.initials: R
authors.lastname: Baldassano
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: 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
chemical_list: D053759:Interleukin-23; D018664:Interleukin-12